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Research ArticleJanuary 26, 2022

Semax, a Synthetic Regulatory Peptide, Affects Copper-Induced Abeta Aggregation and Amyloid Formation in Artificial Membrane Models
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Michele F.M. Sciacca*
Michele F.M. Sciacca
Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Via Paolo Gaifami, 18, Catania 95126, Italy
*Email: [email protected]
More by Michele F.M. Sciacca
https://orcid.org/0000-0002-9981-3321
Irina Naletova
Irina Naletova
Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Via Paolo Gaifami, 18, Catania 95126, Italy
More by Irina Naletova
Maria Laura Giuffrida
Maria Laura Giuffrida
Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Via Paolo Gaifami, 18, Catania 95126, Italy
More by Maria Laura Giuffrida
Francesco Attanasio*
Francesco Attanasio
Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Via Paolo Gaifami, 18, Catania 95126, Italy
*Email: [email protected]
More by Francesco Attanasio

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ACS Chemical Neuroscience

Cite this: ACS Chem. Neurosci. 2022, 13, 4, 486–496

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https://doi.org/10.1021/acschemneuro.1c00707

Published January 26, 2022

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Abstract

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Alzheimer’s disease, the most common form of dementia, is characterized by the aggregation of amyloid beta protein (Aβ). The aggregation and toxicity of Aβ are strongly modulated by metal ions and phospholipidic membranes. In particular, Cu²⁺ ions play a pivotal role in modulating Aβ aggregation. Although in the last decades several natural or synthetic compounds were evaluated as candidate drugs, to date, no treatments are available for the pathology. Multifunctional compounds able to both inhibit fibrillogenesis, and in particular the formation of oligomeric species, and prevent the formation of the Aβ:Cu²⁺ complex are of particular interest. Here we tested the anti-aggregating properties of a heptapeptide, Semax, an ACTH-like peptide, which is known to form a stable complex with Cu²⁺ ions and has been proven to have neuroprotective and nootropic effects. We demonstrated through a combination of spectrofluorometric, calorimetric, and MTT assays that Semax not only is able to prevent the formation of Aβ:Cu²⁺ complexes but also has anti-aggregating and protective properties especially in the presence of Cu²⁺. The results suggest that Semax inhibits fiber formation by interfering with the fibrillogenesis of Aβ:Cu²⁺ complexes.

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Introduction

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Alzheimer’s disease represents the most common neurodegenerative disease. (1) According to data from the World Alzheimer Report, over 46.8 million people were affected by dementia worldwide in 2015, with a prevision of a doubling of this number in the next 20 years. (2,3) To date, despite the intense research activity, the etiology of the pathology is not fully understood.

The principal hallmark of Alzheimer’s disease is the appearance in the hippocampal region of the brain (4) of proteinaceous deposits inside neuronal cells, called neurofibrillary tangles, mainly constituted by fibrillar aggregates of phosphorylated tau protein, (5) and in the extracellular space, called amyloid plaques, mainly constituted by fibrillar aggregates of amyloid beta protein (Aβ). (6) Amyloid β protein is the final product of the aberrant cleavage of amyloid precursor protein (APP). (7)

It was proposed that an abnormally high concentration of Aβ could result in aggregation into a β-sheet rich structure, the starting point of the fibrillogenesis of Aβ. (8) Aggregation is a complex mechanism that starts with the formation of oligomeric species, suggested to be the more toxic species for cells, (9,10) that undergo conformational reorganization into protofibrils and fibrils. Monomeric and fibrillar forms have been demonstrated to be, respectively, protective (11) or mostly inert (12) for neuronal cells. It is widely recognized that metal ions, in particular copper, are involved in the aggregation process of several protein and amyloidogenic peptides. (13−15)

A pivotal role in Aβ fibrillogenesis is played by phospholipidic membranes and metal ions. (16−19) Neuronal cell membranes are not only the target of amyloid toxicity but also an active actor that can drive Aβ toward the formation of toxic species. (20−24) Great efforts were put in evaluating the role of metal ions, in particular Cu²⁺ and to a lesser extent Zn²⁺, considering the importance of these two metal ions in the normal brain function and the presence of these metals in the amyloid plaques. (25−27) Over the years, a great amount of data has been collected on the interaction and complex formation of Aβ and Cu²⁺. Although results are often contradictory, there is a general consensus that the Aβ/Cu²⁺ complex formation drives and modulates the final end of the aggregation process. (16−19) It was demonstrated that, depending on the protein/ion ratio, the aggregation is driven toward amorphous or fibrillar structures. (17,28−32) In the last decade, many peptide inhibitors of Aβ aggregation have been proposed (33−36) and evaluated for the treatment of AD. (37) Peptides capable of both preventing fibril formation and sequestering free Cu²⁺ ion are particularly interesting. (38−45)

Heptapeptide ACTH(4–7)-PGP, also known as Semax (Met-Glu-His-Phe-Pro-Gly-Pro), is an ACTH-like peptide, in particular an analog of the endogenous regulatory peptide ACTH (4–10) (Met-Glu-His-Phe-Arg-Trp-Gly); biological effect studies on Semax showed that this peptide has pronounced nootropic, neuroprotective, and neurotrophic properties, (46−50) stimulating learning and memory formation in rodents and humans. (46,51,52) It has been suggested that these effects of Semax are associated with its ability to modulate the expression of neurotrophins. (53,54) Semax’s ability to form stable complexes with copper(II) and to prevent the copper-induced cytotoxicity on SH-SY5Y neuroblastoma and RBE4 endothelial cell lines was also investigated. (55,56) The marked nootropic, neuroprotective, and neurotrophic effects of Semax could make this peptide a promising candidate for the prevention and treatment of pathologies of the central nervous system.

To date, there is a lack of information about the ability of this peptide to inhibit or hamper Aβ fibril formation. Here, we performed a combination of biophysical and biological experiments to test the ability of Semax to modulate fiber formation in both the presence and absence of Cu²⁺ and model membranes. We found that Semax is able, in a concentration-dependent way, to inhibit fiber formation both in the buffer and in the presence of model membranes. Differential scanning calorimetry allowed us to evaluate how Semax modulates over time the interaction of amyloid β-1-40 (Aβ_1–40) with the hydrophobic core of phospholipidic membranes in the presence of Cu²⁺ ions. Finally, we show that Semax exerts its anti-aggregation properties and is able to prevent membrane disruption, especially in the presence of metal ions. The results suggest that Semax could modulate the Aβ fiber formation process. Although more in-depth details are needed, this first study about the anti-aggregating properties of Semax provides promising results and could represent the starting point for a complete evaluation of Semax as an anti-AD drug candidate.

Results and Discussion

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Thioflavin T Assay in the Buffer Reveals Anti-aggregating Properties of Semax in the Presence of Cu²⁺

Aβ_1–40 undergoes fibrillation in the buffer solution, showing a classical sigmoidal curve of Thioflavin T (ThT) fluorescence (Figure 1, black line). The ThT kinetic curve is characterized by a lag time (t_lag, the time in which ThT fluorescence reaches 5% of its maximum), dominated by the formation of oligomeric species not detectable by ThT, followed by an elongation phase, in which pre-fibrillar structures elongate to fiber, normally characterized by a time to half (t_1/2, the time in which the ThT fluorescence reaches half of its maximum value) and, finally, a plateau region in which the equilibrium is reached and the ThT fluorescence reaches its maximum value I_max (Figure S1 in the Supporting Information). The ThT kinetic curve may be analyzed by using a sigmoidal curve:

(1)

in which I_max = maximum fluorescence intensity, t_1/2 = time to half, and τ = elongation time constant. The apparent time constant k_app is given by 1/τ, and the lag time is defined as t_lag = t_1/2 – 2τ. (57)

Figure 1. Thioflavin T assay in the MOPS buffer. ThT traces of samples containing Aβ_1–40 20 μM alone (black curve) and in the presence of Cu²⁺ 20 μM (orange curve), Semax 20 μM (gray curve), Semax 100 μM (yellow curve), Cu²⁺ 20 μM/Semax 20 μM (blue curve), and Cu²⁺ 20 μM/Semax 100 μM (green curve). All the experiments were performed at 37 °C in the 10 mM MOPS buffer and 100 mM NaCl at pH 7.4. All traces are the average of three independent experiments.

Semax at an equimolar ratio (Figure 1, gray curve) does not significantly perturb any of the kinetic parameters of the Aβ_1–40 fibrillogenesis process in our condition. Interestingly, the increase of the Semax amount to a ratio of 1:5 (Figure 1, yellow curve) leads to higher t_lag and t_1/2 (Table 1). Moreover, we also observed a significant decrease in I_max. Thus, Semax shows concentration-dependent anti-aggregating properties. Whether the inhibition of aggregation occurs by the interaction and stabilization of monomeric or oligomeric species is not clear from ThT experiments. However, the longer lag phase followed by faster elongation rate observed for samples containing Semax at higher concentrations (Table 1) suggests the stabilization of oligomers as the more probable mechanism.

Table 1. Kinetic Parameters Derived from ThT Experiments Shown in Figure 1 ^a

sample	I_max (A.U.)	t_lag (min)	t_1/2 (min)	k_app (min^–1)	τ (min)
Aβ_1–40 20 μM	26.2 ± 0.1	407.2 ± 1.3	457.4 ± 1.2	10·10^–3 ± 1.0·10^–4	100.4 ± 6.2
Aβ_1–40 20 μM/Cu²⁺ 1:1	11.9 ± 0.1	129.7 ± 0.8	141.0 ± 0.5	4.4·10^–2 ± 9.5·10^–4	22.5 ± 9.1
Aβ_1–40 20 μM/Semax 1:1	25 ± 0.1	372.8 ± 2.3	430.9 ± 1.5	8.6·10^–3 ± 9.9·10^–5	116.2 ± 10.2
Aβ_1–40 20 μM/Semax 1:5	18.3 ± 0.1	577.8 ± 3.2	601.5 ± 2.7	2.1·10^–2 ± 1.0·10^–3	47.3 ± 7.4
Aβ_1–40 20 μM/Cu²⁺/Semax 1:1:1	25.7 ± 0.1	344.6 ± 2.5	412.2 ± 2.0	7.4·10^–3 ± 9.6·10^–5	135.1 ± 9.7
Aβ_1–40 20 μM/Cu²⁺/Semax 1:1:5	15.5 ± 0.2	544.4 ± 7.3	582.2 ± 6.1	1.3·10^–2 ± 9.4·10^–4	75.6 ± 13.1

^{^a}

ThT curves were fitted by using the equation . Lag time was calculated as t_lag = t_1/2 – 2τ, and k_app was given by 1/τ. Results are the average of three independent experiments.

It is known that Cu²⁺ ions interact with Aβ_1–40 in the 1–16 region, (58,59) forming a complex and influencing the aggregation process in a concentration-dependent way. (17,60) The addition of an equimolar amount of Cu²⁺ ions to samples containing Aβ_1–40 (Figure 1, orange curve) results in a faster fiber formation process with a significant decrease of t_lag and t_1/2. Moreover, we observe a decrease of the maximum intensity of ThT signal (I_max), as shown in Table 1. A possible explanation is that the presence of Cu²⁺ ion leads to a rapid formation of oligomeric species, which rapidly evolve to mature fibers, with a higher elongation rate than Aβ_1–40 alone, as evidenced by the increase in the growth rate constant (k) and a lower elongation time constant (τ) (Table 1). This behavior is consistent with data reported in the literature; indeed, an equimolar amount of Cu²⁺ is reported to reduce the lag phase (61) with the appearance of spherical amorphous aggregates and few fibrillar structures. (62)

Semax forms stable complexes with Cu²⁺ ions, with a conditional dissociation constant (^cKd) of 1.3·10^–15 M at pH 7.4. (55) Since the Aβ_1–40:Cu²⁺ complex K_d value is in the nanomolar range, (63−66) adding Semax to the samples containing Aβ_1–40 and Cu²⁺ should result in a ThT curve very similar to that observed for Aβ_1–40 only. As expected, the sample containing Aβ_1–40/Cu²⁺/Semax 1:1:1 (Figure 1, blue curve) shows a kinetic profile and kinetic parameters very similar to those obtained for Aβ_1–40 only (Table 1). This evidence confirms that Semax strongly interacts with the Cu²⁺ ion, preventing the formation of Aβ_1–40:metal complexes. An interesting result is observed when Semax is added in a 5:1 ratio (Figure 1, green curve). We observed an increase in the t_lag and t_1/2 similar to that for the sample in the absence of Cu²⁺ ions but a further decrease in the I_max (Table 1), meaning a decrease of the total amount of fiber formed. This evidence suggests that an interaction between the complex Semax:Cu²⁺ and Aβ_1–40 is occurring.

Semax Reduces the Abeta Oligomers Levels

Soluble Aβ oligomers are considered the main neurotoxic species in the development of Alzheimer’s disease. Small oligomers can be formed early in AD progression with a strong correlation between their cortical level and cognitive decline. (67)

We investigate the ability of Semax to interfere with the early phase of Aβ aggregation by incubating the compound with monomeric forms of amyloid-β 1–42 (Aβ₁₋₄₂) for 48 h at low temperature and under gentle rotation to slow the rate of reaction (Figure 2). In this condition, Aβ_1–42 is known to oligomerize, forming species with a typical electrophoresis pattern of low molecular weight (monomers, dimers, and tetramers) and high molecular weight bands ranging from 50 to 200 kDa, often appearing as a smear. We used the N-terminus-specific 6E10 Aβ_1–42 antibody to detect different sizes of aggregated species.

Figure 2. (A) Representative western blot of Aβ_1–42 oligomers (o Aβ) prepared in the presence of Semax (1:5) and/or copper (1:1). Aβ_1–42 incubated alone was also prepared as the control. Samples were loaded onto a 4–12% Bis–Tris SDS-PAGE gel and blotted with anti-Aβ N-terminal 1–16 mouse monoclonal antibody 6E10 (1:500). Densitometric analysis of (B) trimeric, (C) tetrameric, and (D) high molecular weight (HMW) bands quantified by the Image Studio software of the Odyssey instrument.

We found that the presence of Semax and/or Cu²⁺ differently affected the normal oligomerization of Aβ_1–42. To quantify the distribution of oligomeric species produced, we measured the signals of trimeric, tetrameric, and high molecular weight bands by densitometric analysis. We found that co-incubation of Aβ_1–42 with Semax, at molar ratio of 1:5, produced a decrease of signal intensity of either low and higher molecular weights bands. A slighter increase was seen in the same molecular weight size in the presence of copper 1:1. Interestingly, the presence of Semax in the Aβ/copper sample was reported to lower the level of all the bands corresponding to Aβ oligomeric species.

Semax Prevents Aβ_1–40 Interaction with the Hydrophobic Core of the Model Membrane in the Presence of Cu²⁺

The lipidic membrane plays a critical role in the aggregation of amyloidogenic protein. (68−70) It is known that the interaction with the hydrophobic core and/or the surface of the membrane could catalyze fibril formation. (71) Typically inneuronal cells, the ratio between zwitterionic and negatively charged phospholipids headgroup is 3:1. To resemble this ratio, we performed differential scanning calorimetry (DSC) to study the interaction of Aβ_1–40 in the presence of model membranes composed of large unilamellar vesicles (LUV) DMPC:DMPS 3:1. DSC is a useful tool that allows the study of the topology and the amount of peptide membrane interaction (72,73) by evaluating the enthalpy (ΔH) and the transition temperature (T) associated with the gel/liquid crystal transition of the phospholipid bilayer. (74) The thermogram of DMPC:DMPS 3:1 LUV shows a single peak (Figure S2, black curve) centered at 27.5 °C and a ΔH of 29.3 kJ mol^–1 (Table S1). The addition of Aβ_1–40 induces a remodulation of the spatial distribution of the lipid (Figure S3A), which is also a function of the temporal evolution of samples (Figure S4A–D). Phase segregation has been observed several times in the literature and depends on the nature of the interaction of a protein or a peptide with the phospholipid bilayer. (72,75−77) In our samples, three distinct peaks appear in the thermogram (Figure S3A). The first, well resolved, at the lower temperature could be assigned to the region of the membrane richer in zwitterionic DMPC. The second and the third ones, which convolute each other, represent regions of the bilayer richer in negatively charged DMPS. Deconvolution of peaks allows one to estimate the region of interaction of the protein (Figure S3B).

At time 0, the main species in the solution are monomeric Aβ. The thermogram of the sample containing Aβ_1–40 alone (Figure S2A, red curve) shows a decrease in the overall ΔH (Table S2), which is the sum of three contributions as explained before. As expected, the presence of Cu²⁺ ions (Figure S2A, green curve) enhances the interaction of Aβ_1–40 with the hydrophobic core of the bilayer as evidenced by the further decrease of the ΔH_tot. By comparing the ΔH of each peak, it appears that the interaction mainly involves the region of the membrane with a lipidic composition similar to that of the reference (3:1), with a significant decrease in ΔH_2, while ΔH₁ and ΔH₃, associated with a region richer in zwitterionic lipid and negatively charged lipid, respectively, remain substantially unaltered (Figure 3A and Table S1). As expected, the addition of Semax, at both 1:1 and 1:5 ratios (Figure 3A, yellow and blue curves), results in thermodynamic parameters (Table S1) very similar to those of the sample containing only Aβ_1–40. This result matches very well with what was observed in ThT experiments, and it is mostly due to the formation of the Semax/Cu²⁺ complex that is more stable than the Aβ_1–40/Cu²⁺ complex.

Figure 3. Comparison of enthalpy contribution. Contribution of ΔH of each peak for LUV DMPC:DMPS in the presence of Aβ_1–40 5 μM, Aβ_1–40 5 μM + Cu²⁺ 5 μM, Aβ_1–40 5 μM + Cu²⁺ 5 μM + Semax 5 μM, and Aβ_1–40 5 μM + Cu²⁺ 5 μM + Semax 25 μM at (A) time 0 and (B) 24 h.

Letting the sample evolve, after 6 h, the main species in the solution are oligomeric or pre-fibrillar species. The thermogram of the sample containing Aβ_1–40 (Figure S2B, red curve) shows a further decrease of ΔH_tot, meaning that the protein is continuing to insert through the lipid hydrophobic tails. In particular, we observed a further decrease of ΔH₂ (Table S2). The sample containing Cu²⁺ (Figure S2B, green curve) also shows a further decrease of ΔH_tot and, in particular, ΔH₂ (Table S2), stronger than that of Aβ_1–40 alone (Figure S5). Interestingly, the addition of Semax seems to inhibit the further insertion of prefibrillar species in the hydrophobic core of the bilayer (Figure S2B, yellow and blue curves). We observed a ΔH_tot higher not only than that of Aβ_1–40/Cu²⁺ but also than that of Aβ_1–40 alone (Table S2). By comparing the contribution of each peak (Figure S5), we observed that the main effect, which is concentration dependent, is on the second peak as evidenced by the values of ΔH₂. This suggests the hypothesis that the Semax/Cu²⁺ complex mainly interacts with oligomeric species of Aβ_1–40 by both retarding their formation and hampering their interaction with the lipidic membrane.

After 24 h, the fiber formation process is completed. The main species in the solution are mature fibers. For each sample, we observed a further significant decrease of the ΔH_tot (Table S3). This could be explained keeping in mind that Aβ_1–40 disrupts the integrity of the model membrane through a two-step mechanism: the first step is the formation of pores, and the second step is correlated with the elongation of the fibers on the membrane surface and the disruption through a detergent-like mechanism. (72) The presence of Cu²⁺ (Figure S2, green curve) dramatically decreased ΔH_tot. Comparing the contribution of single peaks (Figure 3B), it is evident that the presence of Cu²⁺ decreases ΔH₃ significantly_, meaning that it enhances the interaction with the region of the membrane richer in negatively charge phospholipids. Interestingly, the presence of Semax (Figure S2, yellow and blue curves), independent of the concentration, hampers the interaction of mature fibrils with the phospholipidic bilayer. In particular, we observed higher values of ΔH₂ than those of samples containing Aβ_1–40 alone or in the presence of Cu²⁺.

The overall results suggest that the presence of Semax modifies the interaction of Aβ_1–40 with the model membrane not only by sequestering Cu²⁺ but by interacting most probably with the oligomers.

Semax Strongly Inhibits Fiber Formation in the Presence of bTLE Model Membranes

Membrane composition as well as the environment plays a critical role in the aggregation process of Aβ. For this reason, we performed experiments in the presence of LUV composed of the brain total lipid extract (bTLE), which resembles neuron lipid composition, dispersed in the artificial cerebrospinal fluid (aCSF) at pH 7.4. Aβ_1–40 in this condition shows the typical sigmoidal curve (Figure 4, black curve) characterized by a t_1/2 of ∼239 min and an I_max of ∼12.7 (Table 2). Semax, added to our samples, shows an interesting concentration-dependent effect. When added in a stoichiometric ratio (Figure 4, gray curve), it does not perturb significantly the kinetics of fiber formation. We observed a small increase in the lag phase and a small decrease of the total mass of fiber formed (Table 2). When Semax is added in a 5:1 ratio (Figure 4, yellow curve), it significantly increases the lag phase (Table 2) but does not reduce the total amount of fiber formed, which is identical to that observed at lower concentrations. This evidence suggests a concentration-dependent interaction of Semax with Aβ_1–40 oligomers.

Figure 4. Thioflavin T assay in the presence of bTLE LUVs. ThT traces of samples containing LUV bTLE 0.2 mg mL^–1 and Aβ_1–40 20 μM alone (black curve) and in the presence of Cu²⁺ 20 μM (orange curve), Semax 20 μM (gray curve), Semax 100 μM (yellow curve), Cu²⁺ 20 μM/Semax 20 μM (blue curve), and Cu²⁺ 20 μM/Semax 100 μM (green curve). All the experiments were performed at 37 °C in aCSF at pH 7.4. All traces are the average of three independent experiments.

Table 2. Kinetic Parameters Derived from ThT Experiments Shown in Figure 4 ^a

sample	I_max (A.U.)	t_lag (min)	t_1/2 (min)	k (min^–1)	τ (min)
Aβ_1–40 20 μM	12.7 ± 0.2	239.0 ± 2.5	439.0 ± 2.8	2.5·10^–2 ± 1.2·10^–3	40.0 ± 2.3
Aβ_1–40 20 μM/Cu²⁺ 1:1	21.5 ± 0.1	814,5 ± 3.2	986.9 ± 3.5	2.8·10^–3 ± 1.0·10^–4	357.1 ± 5.2
Aβ_1–40 20 μM/Semax 1:1	10.5 ± 0.5	353.3 ± 5.6	462.0 ± 6.6	4.6·10^–2 ± 1.8·10^–3	21.7 ± 3.6
Aβ_1–40 20 μM/Semax 1:5	10.5 ± 0.5	806.6 ± 4.3	865.4 ± 4.1	8.5·10^–2 ± 2.2·10^–3	11.8 ± 5.1
Aβ_1–40 20 μM/Cu²⁺/Semax 1:1:1	3.7 ± 0.2	554.7 ± 2.1	706.2 ± 1.8	3.3·10^–3 ± 1.2·10^–4	303.0 ± 6.2
Aβ_1–40 20 μM/Cu²⁺/Semax 1:1:5	5.8 ± 0.1	1407.7 ± 10.6	1635.0 ± 12.4	2.2·10^–3 ± 2.3·10^–4	454.5 ± 13.5

^{^a}

ThT curves were fitted by using the equation . Lag time was calculated as t_lag = t_1/2 – 2τ, and k_app was given by 1/τ. Results are the average of three independent experiments.

The presence of Cu²⁺ 1:1 alone (Figure 4, orange curve) totally modifies the kinetics of fiber formation. It is evident that the presence of metal ions retards fiber formation with a significant increase of lag phase, reduces the elongation rate, but induces the formation of more fiber at the end of the process (Table 2). Interestingly, the presence of Semax in samples containing Cu²⁺ ions seems to inhibit, almost completely, the Aβ_1–40 fiber formation (Table 2) at both lower (Figure 4, blue curve) and higher (Figure 4, green curve) concentrations. This result was unexpected since a simple Semax/Cu²⁺ complex formation should result in a behavior similar to that observed in the absence of metal ions or, at least, for the sample containing a higher amount of Semax, to that observed in the presence of Semax only. In our experimental condition, Semax was added after the Aβ_1–40/Cu²⁺ complex formation; thus, it is reasonable to think that Semax not only subtracts Cu²⁺ from the Aβ_1–40/Cu²⁺ complex but is able to interact and stabilize oligomers formed starting from these complexes. Although beyond the purpose of this work, we try to prove this hypothesis by letting the Semax/Cu²⁺ complex interact with Aβ_1–40 (Figure S6). In these conditions, what we observed is a completely different result, with the kinetics of fiber formation more similar to those observed for the sample containing Aβ_1–40 only. This result strengthens our hypothesis, which in any case needs more in-depth studies to be confirmed.

Semax Prevents Membrane Disruption Induced by Aβ_1–40

The mechanism of model membrane disruption induced by Aβ_1–40 could be studied by using a dye leakage experiment. It was demonstrated that Aβ_1–40, as well as other amyloidogenic proteins, is able to disrupt the model membrane with a two-step mechanism. (78−81) In particular, the second step of membrane disruption is correlated with the elongation of the fibers on the membrane surface through a detergent-like mechanism. (78) Here we performed a dye leakage assay on samples containing bTLE LUV filled with 5(6)-carboxyfluorescein. Aβ_1–40 alone (Figure 5, black curve) shows a leakage of ∼68% with a t_1/2 of ∼688 min (Table 3), a value comparable with ThT t_1/2 in the same condition. Interestingly, Semax reduces in a concentration-dependent way the total amount of membranes leaked. In particular, the total amount of membrane disrupted is ∼52% when added in a 1:1 ratio (Figure 5, gray curve) and ∼31% when added in 5:1 ratio (Figure 5, yellow curve). These results match very well with those observed with the ThT assay, also in terms of t_1/2 (Table 3), which are comparable to those of fiber formation. Semax, consistent with what was observed in ThT experiments, seems to protect the membrane from disruption induced by Aβ_1–40.

Figure 5. Dye leakage assay in the presence of bTLE LUVs. Dye release for samples containing LUV bTLE 0.2 mg mL^–1 and Aβ_1–40 20 μM alone (black curve) and in the presence of Cu²⁺ 20 μM (orange curve), Semax 20 μM (gray curve), Semax 100 μM (yellow curve), Cu²⁺ 20 μM/Semax 20 μM (blue curve), and Cu²⁺ 20 μM/Semax 100 μM (green curve). All the experiments were performed at 37 °C in aCSF at pH 7.4. All traces are the average of three independent experiments.

Table 3. Parameters Derived from Dye Leakage Experiments Shown in Figure 5 ^a

sample	F_max	t_1/2 (min)
Aβ_1–40 20 μM	0.68 ± 0.05	688 ± 2
Aβ_1–40 20 μM/Cu²⁺ 1:1	0.68 ± 0.06	733 ± 3
Aβ_1–40 20 μM/Semax 1:1	0.52 ± 0.05	712 ± 2
Aβ_1–40 20 μM/Semax 1:5	0.31 ± 0.09	1631 ± 2
Aβ_1–40 20 μM/Cu²⁺/Semax 1:1:1	0.26 ± 0.07	1643 ± 3
Aβ_1–40 20 μM/Cu²⁺/Semax 1:1:5	0.15 ± 0.03	1604 ± 2

^{^a}

Dye leakage curves were fitted by using the Boltzmann curve. Results are the average of three independent experiments.

The presence of Cu²⁺ (Figure 5, orange curve) does not significantly modify membrane disruption (Table 3). But, consistent with ThT experiments, the addition of Semax at both lower (Figure 5, blue curve) and higher (Figure 5, green curve) concentrations significantly reduces the total amount of membrane disrupted (Table 3) to ∼26 and ∼15%, respectively, with t_1/2 comparable to that observed in ThT experiments. Thus, the whole results strengthen the hypothesis that Semax could interfere with oligomeric species formed by Aβ_1–40, which in turn are responsible for the kinetics of fiber formation and the consequent disruption of model membranes.

Semax Rescues Abeta and Cu-Associated Abeta Toxicity

It has previously been shown that Aβ_1–42 oligomeric aggregates form insoluble amyloid deposits in the brain and hippocampus and exhibit neurotoxic effects in in vitro and in vivo models, leading to the cognitive dysfunction prevalent in the pathogenesis of AD. (82,83) Thus, to assess the cytotoxicity of the oligomeric species, the effect of Aβ_1–42 at different preparations of oligomerization on the viability of d-SH-SY5Y cells was investigated via an MTT assay (Figure 6). Cells were treated for 48 h with Aβ_1–42 that was pre-incubated for 48 h with/without Semax or Cu²⁺ (see Materials and Methods). In agreement with previously reported results, (33) we found a decrease of d-SH-SY5Y cell viability after 48 h treatment with 5 μM Aβ_1–42 oligomers. According to the data observed in the above experiments showing Semax protection against Aβ_1–42 oligomer stress, the MTT assay reveals that the presence of exogenous Aβ_1–42 oligomers decreases cell viability up to 32%. Noteworthily, the Aβ_1–42 oligomers prepared in the presence of Semax or/and Cu²⁺ (see Materials and Methods) show a significant effect on cell viability, reducing toxicity by more than 22% in the case of Semax alone and 20% in the case of Semax with Cu²⁺. Another set of experiments was performed to understand the effect of Semax on the toxicity of already formed Aβ_1–42 oligomers. First, we prepared oligomers and then we added Semax with/without copper to the cells. As Figure 6 shows, just as in the case of oligomers preincubated for 48 h in the presence of Semax or Semax-Cu(II) and then added to the d-SH-SY5Y cells, the Semax in this case also protects the cells from the toxicity of the already pre-formed oligomers, reducing Aβ_1–42-induced cell toxicity by up to 90% in both the case with and that without copper.

Figure 6. Viability of d-SH-SY5Y cells after 48 h of incubation with 5 μM differently pre-incubated Aβ_1–42 oligomers with/without Semax and Cu²⁺. Results are presented as mean ± SD with n = 8 for each condition (***p ≤ 0.001with respect to untreated control; ##p ≤ 0.01 with respect to Aβ_1–42 treatment).

Conclusions

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In summary, we performed a series of biophysical experiments that show that the heptapeptide ACTH(4–7)-PGP (Semax) is able to inhibit, in the absence of the model membrane, Aβ fiber formation. In particular, we showed that in the presence of Cu²⁺ ions, Semax is able not only to sequester metal ions, inhibiting Aβ:Cu²⁺ complex formation, but also to interact, most probably, with Aβ:Cu²⁺ oligomers, retarding the formation of protofibrillar and fibrillar species. DSC results showed that the heptapeptide modulates the interaction of Aβ:Cu²⁺ with the hydrophobic core of the model membrane, preventing or retarding the insertion of prefibrillar species in the hydrophobic core of the model membrane. This finding is corroborated by the evidence that in the presence of the model membrane of bTLE, Semax could by itself inhibit fiber formation but exerts the maximum of its anti-aggregating properties in the presence of Cu²⁺ ions. This suggests that the heptapeptide interacts differently with monomeric/oligomeric species of Aβ and Aβ:Cu²⁺ complexes. This different behavior is confirmed by dye leakage experiments that, according to the ThT assay, showed a protective role of Semax. Finally, the MTT assay revealed that Semax or the Semax:Cu²⁺ complex protects cells from the toxicity of Aβ_1–42 oligomers. More in-depth experiments should be done especially to investigate the effect of Semax on ROS production, which is known to increase as an effect of Aβ:Cu²⁺ interaction.

Material and Methods

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Materials

Aβ_1–40 and Aβ₁₋₄₂ was purchased from Bachem (Bubendorf, Switzerland) with a purity ≥95%. Semax (H-Met-Glu-His-Phe-Pro-Gly-Pro-OH) was purchased from Sigma Aldrich (St. Louis, MO, USA) with a purity ≥98%. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine (DMPS), and brain total lipid extract (bTLE) were purchased from Avanti Polar Lipids (Alabaster, AL, USA). Thioflavin T, 6-carboxyfluorescein, NaCl, NaHCO₃, KCl, NaH₂PO₄, MgCl₂, glucose, CaCl₂, and all other salts were purchased from Sigma-Aldrich (St. Louis, MO, USA).

Preparation of the Artificial Cerebrospinal Fluid

The buffer used for some experiments is the artificial cerebrospinal fluid (aCSF). aCSF was prepared by dissolving in Millipore water 119 mM NaCl, 26.2 mM NaHCO₃, 2.5 mM KCl, 1 mM NaH₂PO₄, 1.3 mM MgCl₂, 10 mM glucose, and 2.5 mM CaCl₂. The final pH was 7.4. The buffer was stored at 4 °C and was stable for at least 3 weeks.

Peptide Preparation

To prevent the presence of any preformed aggregates, Aβ_1–40 was initially dissolved in HFIP at a concentration of 1 mg/mL and then lyophilized overnight. To be used for the experiments, the lyophilized powder was initially dissolved in NH₃OH 6 M to obtain a stock solution with a final concentration of 250 μM. The concentration of Aβ was determined by using the absorption of tyrosine at λ 280 nm (ε = 1490 M^–1 cm^–1). The Semax concentration was calculated by copper UV titration. According to equilibrium studies, (55) Semax forms a single complex species (100%), the [CuLH–2] ^2–, with the donor atoms around copper arranged in a 4 N planar coordination mode, at pH 7.4 with a conditional dissociation constant (^cKd) of 1.3 × 10^–15 M. The Cu(NO₃)₂ stock solution was prepared and standardized with ethylenediaminetetraacetic acid, as reported by Flashka. (84) Each stock solution was used immediately after preparation by diluting in the opportune buffer solution to reach the concentration needed for experiments.

LUV Preparation

We used large unilamellar vesicles (LUVs) composed of a mixture of zwitterionic and negatively charged lipids (DMPC and DMPS in 3:1 ratio) or the brain total lipid extract (bTLE). Model membranes were prepared as described elsewhere. (85) Briefly, appropriate aliquots of lipid stock solutions in chloroform were dried by using a stream of dry nitrogen and evaporated overnight under high vacuum to dryness in a round-bottomed flask. Initially, multilamellar vesicles (MLVs) were obtained by hydrating the lipid film with an appropriate amount of buffer (aCSF buffer 10 mM (pH 7.4) or MOPS buffer 10 mM and 100 mM NaCl (pH 7.4)) and dispersing by vigorous stirring. MLVs were then extruded through polycarbonate filters (pore size = 100 nm, Nuclepore, Pleasanton, CA) mounted in a mini-extruder (Avestin, Ottawa, Canada) fitted with two 0.5 mL Hamilton gastight syringes (Hamilton, Reno, NV) to obtain LUVs. Samples were typically subjected to 23 passes through two filters in tandem and as recommended elsewhere. (86)

ThT Measurements

The kinetics of aβ fiber formation were measured using the Thioflavin T (ThT) assay. Samples were prepared by diluting, in MOPS buffer or in a solution containing bTLE LUVs, the aβ stock solution to reach the final concentration. Semax and/or copper were added from a stock solution to the indicated concentration. Thioflavin T was then added to a final concentration of 40 μM. Experiments were carried out in Corning 96-well non-binding surface plates. Time traces were recorded using a Varioskan (ThermoFisher, Waltham, MA) plate reader using a λ_ex of 440 nm and a λ_em of 485 nm at 37 °C, shaking the samples for 10 s before each read. All ThT curves represent the average of three independent experiments.

Dye Leakage Measurements

Membrane leakage experiments were performed by measuring the leakage of 6-carboxyfluorescein dye from LUVs. Dye-filled bTLE LUVs were prepared by hydrating the dry lipid film with the buffer solution containing 6-carboxyfluorescein (80 mM 6-carboxyfluorescein, pH 7.4) according to the procedure described above. Non-encapsulated 6-carboxyfluorescein was removed by eluting the solution containing LUVs through a Sephadex G50 gel exclusion column (Sigma-Aldrich, St. Louis, MO) using the buffer solution. The final concentration of lipids was checked by using the Stewart assay as described elsewhere. (87) Membrane damage was quantified by the increase in fluorescence emission intensity of 6-carboxyfluorescein due to its dilution (de-quenching) in the buffer as a result of the membrane leakage. Time traces were recorded in Corning 96-well non-binding surface plates using a Varioskan (ThermoFisher, Waltham, MA) plate reader using a λ_ecc of 490 nm and a λ_em of 510 nm at 37 °C, shaking the samples for 10 s before each read. All curves represent the average of three independent experiments.

DSC Experiments

DSC runs of DMPC/DMPS 3:1 LUVs were carried out on a Nano-DSC (TA Instruments, Inc., New Castle, DE) apparatus. Lipid samples were degassed by vacuum and then heated from 20 to 40 °C at a scan rate of 1 °C min^–1. A lipid/peptide ratio of 20:1 was used in all the experiments. An extra external pressure of about 3 atm was applied on the solution to prevent the formation of bubbles during heating. The MOPS buffer solution 10 mM and 100 mM NaCl (pH 7.4) were used as reference. Heat capacity curves (Cp) were obtained by subtracting the buffer–buffer baseline from raw DSC data. All DSC runs were performed immediately after the preparation of samples and after 6 and 24 h to observe if kinetic effects are present.

Anti-oligomerization Assay

Aβ_1–₄₂ oligomers were prepared as previously described (11) from synthetic Aβ₁_–₄₂ following the protocol of monomerization. Aβ₁_–₄₂ (0.3 mg) was firstly dissolved in 5 mM DMSO. A solution of 100 μM Aβ_1–42 in ice-cold DMEM F-12 without phenol red was prepared and allowed to oligomerize for 48 h at 4 °C according to the Lambert protocol (88) with some modifications as previously described. (11) To evaluate the ability of SEMAX and/or copper to interfere with Aβ oligomer formation, samples of Aβ_1–42 were incubated in the presence or absence of each compound (Aβ/ligand ratios of 1:5 and 1:1 respectively). After 48 h incubation, Aβ/ligand compounds were analyzed for their content of Aβ oligomers.

Western Blot Analysis

After incubation, the amount and size of Aβ aggregates were determined by western blot analysis. Unheated samples (25 μL) were loaded onto precast Bis–Tris gel (Bolt 4–12%, Life Technologies) with 2-morpholin-4-ylethanesulfonic acid (MES). Samples were transferred onto a nitrocellulose membrane (0.2 mm, Hybond ECL, Amersham Italia) by a wet transfer unit (Mini Blot Module, Life Technologies). Membranes were blocked in the Odyssey blocking buffer (Li-COR Biosciences) and incubated at 4 °C overnight with the mouse monoclonal anti-amyloid-β antibody against N-terminal 1–16 peptide (1:1000) (6E10, Covance). Goat anti-mouse secondary antibodies labeled with IR dye 800 (1:25,000) were used at RT for 45 min. Hybridization signals were detected with the Odyssey CLx Infrared Imaging System (LI-COR Biosciences Lincoln, Nebraska, USA), and densitometric analysis was performed by the use of the Image Studio software.

Cell Maintenance and Treatment Protocol

The human neuroblastoma cell line (SH-SY5Y) was cultivated in the full medium, i.e., DMEM F-12 supplemented with 10% FBS, 2 mM l-glutamine, and 100 μg mL^–1 streptomycin, in tissue-culture treated Corning flasks (Sigma-Aldrich). For differentiation of SH-SY5Y (d-SH-SY5Y), cells were seeded at a density of 1.5 × 10⁴ cells/well and neuronal differentiation was induced by treatment for 7 days with 10 μM retinoic acid (RA) in DMEM F-12 medium supplemented with 0.5% of FBS. The cell culture was grown in tissue-culture treated Corning flasks (Sigma-Aldrich) in a humidified atmosphere (5% CO₂) at 37 °C (HeraCell 150C incubator, Heraeus, Hanau, Germany).

MTT Assay

Aβ_1–42 peptide oligomers were prepared as described in ″Anti-oligomerization Assay″ with/without Semax and copper. d-SH-SY5Y cell viability was tested by incubation with 5 μM Aβ_1–42 samples for 48 h in DMEM supplemented with 0.5% of FBS without RA. The viable cells were quantified by the reaction with MTT. After 90 min, the reaction was stopped by adding DMSO, and absorbance was measured at 570 nm (Varioskan Flash Spectral Scanning Multimode Readers, Thermo Scientific, Waltham, MA, USA); the results were expressed as % of viable cells. The experiments were repeated with n = 8, and results were expressed as mean ± SD.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.1c00707.

DSC thermograms, thermodynamic data and comparison, and ThT in the presence of model membranes (PDF)

cn1c00707_si_001.pdf (282.74 kb)

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Author Information

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Corresponding Authors
- Michele F.M. Sciacca - Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Via Paolo Gaifami, 18, Catania 95126, Italy; https://orcid.org/0000-0002-9981-3321; Email: [email protected]
- Francesco Attanasio - Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Via Paolo Gaifami, 18, Catania 95126, Italy; Email: [email protected]
Authors
- Irina Naletova - Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Via Paolo Gaifami, 18, Catania 95126, Italy
- Maria Laura Giuffrida - Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Via Paolo Gaifami, 18, Catania 95126, Italy
Author Contributions
M.F.M.S. and F.A. designed the research. M.F.M.S. and F.A. performed and analyzed DSC and spectrofluorimetric experiments. M.L.G. and I.N. performed and analyzed the western blot and MTT experiments. M.F.M.S. and F.A. wrote the manuscript.
Notes
The authors declare no competing financial interest.

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Characterization of sol. oligomeric amyloid β (Aβ) species in the brains of Alzheimer's disease (AD) patients and transgenic models has raised the possibility that different conformations of Aβ may contribute to AD pathol. via different mechanisms. To characterize the toxic effect of different Aβ conformations, we tested side by side the effect of well characterized Aβ oligomers (AβOs), Aβ-derived diffusible ligands (ADDLs), and fibrillar Aβ (Aβf) prepns. in human cortical neurons (HCNs). Both AβOs and ADDLs bind rapidly and with high affinity to synaptic contacts and cellular membranes. AβOs (5 μM) induced rapid and massive neuronal death. Calcium influx accelerated, but was not required for, AβO toxicity. AβOs elicited a stereotyped succession of cellular changes consistent with the activation of a mitochondrial death apoptotic pathway. At low concns. AβOs caused chronic and subtler mitochondrial alterations but minimal cell death. ADDLs induced similar toxic changes as AβOs but on a fivefold longer time scale. Higher concns. of Aβf and longer incubation times were required to produce widespread neuritic dystrophy but modest HCN cell death. Thus various Aβ species may play relevant roles in AD, causing neurotoxicity by distinct non-overlapping mechanisms affecting neuronal function and viability over multiple time courses.
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Giuffrida, M. L.; Caraci, F.; Pignataro, B.; Cataldo, S.; Bona, P. D.; Bruno, V.; Molinaro, G.; Pappalardo, G.; Messina, A.; Palmigiano, A.; Garozzo, D.; Nicoletti, F.; Rizzarelli, E.; Copani, A. β-Amyloid Monomers Are Neuroprotective. J. Neurosci. 2009, 29, 10582– 10587, DOI: 10.1523/JNEUROSCI.1736-09.2009
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β-Amyloid monomers are neuroprotective
Giuffrida, Maria Laura; Caraci, Filippo; Pignataro, Bruno; Cataldo, Sebastiano; De Bona, Paolo; Bruno, Valeria; Molinaro, Gemma; Pappalardo, Giuseppe; Messina, Angela; Palmigiano, Angelo; Garozzo, Domenico; Nicoletti, Ferdinando; Rizzarelli, Enrico; Copani, Agata
Journal of Neuroscience (2009), 29 (34), 10582-10587CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
The 42-aa-long β-amyloid protein-Aβ1-42-is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). Data from AD brain, transgenic APP (amyloid precursor protein)-overexpressing mice, and neuronal cultures treated with synthetic Aβ peptides indicate that self-assocn. of Aβ1-42 monomers into sol. oligomers is required for neurotoxicity. The function of monomeric Aβ1-42 is unknown. The evidence that Aβ1-42 is present in the brain and CSF of normal individuals suggests that the peptide is physiol. active. Here we show that synthetic Aβ1-42 monomers support the survival of developing neurons under conditions of trophic deprivation and protect mature neurons against excitotoxic death, a process that contributes to the overall neurodegeneration assocd. with AD. The neuroprotective action of Aβ1-42 monomers was mediated by the activation of the PI-3-K (phosphatidylinositol-3-kinase) pathway, and involved the stimulation of IGF-1 (insulin-like growth factor-1) receptors and/or other receptors of the insulin superfamily. Interestingly, monomers of Aβ1-42 carrying the Arctic mutation (E22G) assocd. with familiar AD were not neuroprotective. We suggest that pathol. aggregation of Aβ1-42 may also cause neurodegeneration by depriving neurons of the protective activity of Aβ1-42 monomers. This "loss-of-function" hypothesis of neuronal death should be taken into consideration when designing therapies aimed at reducing Aβ burden.
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Wu, W.; Liu, Q.; Sun, X.; Yu, J.; Zhao, D.; Yu, Y.; Luo, J.; Hu, J.; Yu, Z.; Zhao, Y.; Li, Y. Fibrillar Seeds Alleviate Amyloid-β Cytotoxicity by Omitting Formation of Higher-Molecular-Weight Oligomers. Biochem. Biophys. Res. Commun. 2013, 439, 321– 326, DOI: 10.1016/j.bbrc.2013.08.088
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Fibrillar seeds alleviate amyloid-β cytotoxicity by omitting formation of higher-molecular-weight oligomers
Wu, Wei-hui; Liu, Qian; Sun, Xun; Yu, Ji-sheng; Zhao, De-sheng; Yu, Ye-ping; Luo, Jun-jie; Hu, Jia; Yu, Zhi-wu; Zhao, Yu-fen; Li, Yan-mei
Biochemical and Biophysical Research Communications (2013), 439 (3), 321-326CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
Amyloid-β (Aβ) peptides can exist in distinct forms including monomers, oligomers and fibrils, consisting of increased nos. of monomeric units. Among these, Aβ oligomers are implicated as the primary toxic species as pointed by multiple lines of evidence. It has been suggested that toxicity could be rendered by the sol. higher-mol.-wt. (high-n) Aβ oligomers. Yet, the most culpable form in the pathogenesis of Alzheimer's disease (AD) remains elusive. Moreover, the potential interaction among the insol. fibrils that have been excluded from the responsible aggregates in AD development, Aβ monomers and high-n oligomers is undetd. Here, we report that insol. Aβ fibrillar seeds can interact with Aβ monomers at the stoichiometry of 1:2 (namely, each Aβ mol. of seed can bind to two Aβ monomers at a time) facilitating the fibrillization by omitting the otherwise mandatory formation of the toxic high-n oligomers during the fibril maturation. As a result, the addn. of exogenous Aβ fibrillar seeds is seen to rescue neuronal cells from Aβ cytotoxicity presumably exerted by high-n oligomers, suggesting an unexpected protective role of Aβ fibrillar seeds.
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Naletova, I.; Nicoletti, V. G.; Milardi, D.; Pietropaolo, A.; Grasso, G. Copper, Differently from Zinc, Affects the Conformation, Oligomerization State and Activity of Bradykinin. Metallomics 2016, 8, 750– 761, DOI: 10.1039/C6MT00067C
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Copper, differently from zinc, affects the conformation, oligomerization state and activity of bradykinin
Naletova, Irina; Nicoletti, Vincenzo G.; Milardi, Danilo; Pietropaolo, Adriana; Grasso, Giuseppe
Metallomics (2016), 8 (8), 750-761CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
The sole role of bradykinin (BK) as an inflammatory mediator is controversial, as recent data also support an anti-inflammatory role for BK in Alzheimer's disease (AD). The involvement of two different receptors (B1R and B2R) could be a key to understand this issue. However, although copper and zinc dyshomeostasis has been demonstrated to be largely involved in the development of AD, a detailed study of the interaction of BK with these two metal ions has never been addressed. In this work, we have applied mass spectrometry, CD as well as computational methods in order to assess if copper and zinc have the ability to modulate the conformation and oligomerization of BK. In addn., we have correlated the chem. data with the effect of metals on the activity of BK analyzed in cell cultures by biochem. procedures. The biochem. analyses on monocyte/macrophage cell culture (THP-1 Cell Line human) in line with the effect of metals on the conformation of BK showed that the presence of copper can affect the signaling cascade mediated by the BK receptors. The results obtained show a further role of metal ions, particularly copper, in the development and outcome of neuroinflammatory diseases. The possible implications in AD are discussed.
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Thakur, A. K.; Srivastava, A. K.; Srinivas, V.; Chary, K. V. R.; Rao, C. M. Copper Alters Aggregation Behavior of Prion Protein and Induces Novel Interactions between Its N- and C-Terminal Regions. J. Biol. Chem. 2011, 286, 38533– 38545, DOI: 10.1074/jbc.M111.265645
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Copper Alters Aggregation Behavior of Prion Protein and Induces Novel Interactions between Its N- and C-terminal Regions
Thakur, Abhay Kumar; Srivastava, Atul Kumar; Srinivas, Volety; Chary, Kandala Venkata Ramana; Rao, Chintalagiri Mohan
Journal of Biological Chemistry (2011), 286 (44), 38533-38545, S38533/1-S38533/9CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
Copper is reported to promote and prevent aggregation of prion protein. Conformational and functional consequences of Cu2+-binding to prion protein (PrP) are not well understood largely because most of the Cu2+-binding studies have been performed on fragments and truncated variants of the prion protein. In this context, we set out to investigate the conformational consequences of Cu2+-binding to full-length prion protein (PrP) by isothermal calorimetry, NMR, and small angle x-ray scattering. In this study, we report altered aggregation behavior of full-length PrP upon binding to Cu2+. At physiol. temp., Cu2+ did not promote aggregation suggesting that Cu2+ may not play a role in the aggregation of PrP at physiol. temp. (37 °C). However, Cu2+-bound PrP aggregated at lower temps. This temp.-dependent process is reversible. Our results show two novel intra-protein interactions upon Cu2+-binding. The N-terminal region (residues 90-120 that contain the site His-96/His-111) becomes proximal to helix-1 (residues 144-147) and its nearby loop region (residues 139-143), which may be important in preventing amyloid fibril formation in the presence of Cu2+. In addn., we obsd. another novel interaction between the N-terminal region comprising the octapeptide repeats (residues 60-91) and helix-2 (residues 174-185) of PrP. Small angle x-ray scattering studies of full-length PrP show significant compactness upon Cu2+-binding. Our results demonstrate novel long range inter-domain interactions of the N- and C-terminal regions of PrP upon Cu2+-binding, which might have physiol. significance.
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Attanasio, F.; Bona, P. D.; Cataldo, S.; Sciacca, M. F. M.; Milardi, D.; Pignataro, B.; Pappalardo, G. Copper(II) and Zinc(II) Dependent Effects on Aβ42 Aggregation: A CD, Th-T and SFM Study. New J. Chem. 2013, 37, 1206– 1215, DOI: 10.1039/C3NJ40999F
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Copper(ii) and zinc(ii) dependent effects on Aβ42 aggregation: a CD, Th-T and SFM study
Attanasio, Francesco; De Bona, Paolo; Cataldo, Sebastiano; Sciacca, Michele F. M.; Milardi, Danilo; Pignataro, Bruno; Pappalardo, Giuseppe
New Journal of Chemistry (2013), 37 (4), 1206-1215CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
Aβ aggregation is a central event in Alzheimer's disease (AD). In vitro evidence indicates that Aβ aggregation and fibrillogenesis are significantly influenced by the employed exptl. conditions. Indeed, although it is widely established that metal ions, such as copper and zinc, have significant effects on the Aβ aggregation process, their actual role in Aβ fibrillogenesis is still debated. In this work the effects of a molar excess of zinc(ii) and/or copper(ii) ions on the Aβ42 aggregation process and the morphol. of the resultant aggregates have been compared in samples exhibiting different initial conformations. CD spectroscopy, Th-T-induced fluorescence and Scanning Force Microscopy (SFM) measurements indicated that both metal ions accelerate the aggregation process, yet significantly affect the morphol. of aggregates. In particular, copper(ii) ions were the most effective in promoting non-fibrillar, amorphous Aβ aggregates. These results further support the hypothesis that an altered distribution of metal ions in neurons might drive alternative Aβ aggregation pathways.
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Lau, T.-L.; Ambroggio, E. E.; Tew, D. J.; Cappai, R.; Masters, C. L.; Fidelio, G. D.; Barnham, K. J.; Separovic, F. Amyloid-Beta Peptide Disruption of Lipid Membranes and the Effect of Metal Ions. J. Mol. Biol. 2006, 356, 759– 770, DOI: 10.1016/j.jmb.2005.11.091
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Amyloid-β Peptide Disruption of Lipid Membranes and the Effect of Metal Ions
Lau, Tong-Lay; Ambroggio, Ernesto E.; Tew, Deborah J.; Cappai, Roberto; Masters, Colin L.; Fidelio, Gerardo D.; Barnham, Kevin J.; Separovic, Frances
Journal of Molecular Biology (2006), 356 (3), 759-770CODEN: JMOBAK; ISSN:0022-2836. (Elsevier B.V.)
β-Amyloid peptide (Aβ), which is cleaved from the larger trans-membrane amyloid precursor protein, is found deposited in the brain of patients suffering from Alzheimer's disease and is linked with neurotoxicity. We report the results of studies of Aβ(1-42) and the effect of metal ions (Cu2+ and Zn2+) on model membranes using 31P and 2H solid-state NMR, fluorescence and Langmuir Blodgett monolayer methods. Both the peptide and metal ions interact with the phospholipid headgroups and the effects on the lipid bilayer and the peptide structure were different for membrane incorporated or assocd. peptides. Copper ions alone destabilize the lipid bilayer and induced formation of smaller vesicles but when Aβ(1-42) was assocd. with the bilayer membrane copper did not have this effect. CD spectroscopy indicated that Aβ(1-42) adopted more β-sheet structure when incorporated in a lipid bilayer in comparison to the assocd. peptide, which was largely unstructured. Incorporated peptides appear to disrupt the membrane more severely than assocd. peptides, which may have implications for the role of Aβ in disease states.
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Weibull, M. G. M.; Simonsen, S.; Oksbjerg, C. R.; Tiwari, M. K.; Hemmingsen, L. Effects of Cu(II) on the Aggregation of Amyloid-β. JBIC, J. Biol. Inorg. Chem. 2019, 24, 1197– 1215, DOI: 10.1007/s00775-019-01727-5
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Effects of Cu(II) on the aggregation of amyloid-β
Weibull, Martina G. M.; Simonsen, Signe; Oksbjerg, Cecilie R.; Tiwari, Manish K.; Hemmingsen, Lars
JBIC, Journal of Biological Inorganic Chemistry (2019), 24 (8), 1197-1215CODEN: JJBCFA; ISSN:0949-8257. (Springer)
A review. Aberrant aggregation of the Aβ protein is a hallmark of Alzheimer's disease (AD), but no complete characterization of the mol. level pathogenesis has been achieved. A promising hypothesis is that dysfunction of metal ion homeostasis, and consequently, the undesired interaction of metal ions with Aβ, may be central to the development of AD. Qual., most data indicate that Cu(II) induces rapid self-assembly of both Aβ40 and Aβ42 during the initial phase of the aggregation, while at longer time scales fibrillation may occur, depending on the exptl. conditions. For Aβ40 and Cu(II):Aβ ≤ 1, most data imply that low concn. of Aβ40 favors nucleation and rapid fibril elongation, while high concn. of Aβ40 favors formation of amorphous aggregates. However, there are conflicting reports on this issue. For Aβ42 and Cu(II):Aβ ≤ 1, there is consensus that the lag time is extended upon addn. of Cu(II). For Cu(II):Aβ > 1, the lag time is increased upon interaction with Cu(II), and in most cases fibrillation is not obsd., presumably because Cu(II) occupies a second more solvent-exposed binding site, which is more prone to form metal ion-bridged species and cause rapid formation of non-fibrillar aggregates. The interesting N-terminally truncated Aβ11-40 with high affinity for Cu(II), exhibits delay of fibrillation upon addn. of 0.4 equiv. Cu(II). In our view, there are still problems achieving reproducible results in this field, and we provide a shortlist of some of the pitfalls. Finally, we propose a consensus model for the effects of Cu(II) on the aggregation kinetics of Aβ.
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Wärmländer, S. K. T. S.; Österlund, N.; Wallin, C.; Wu, J.; Luo, J.; Tiiman, A.; Jarvet, J.; Gräslund, A. Metal Binding to the Amyloid-β Peptides in the Presence of Biomembranes: Potential Mechanisms of Cell Toxicity. JBIC, J. Biol. Inorg. Chem. 2019, 24, 1189– 1196, DOI: 10.1007/s00775-019-01723-9
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Metal binding to the amyloid-β peptides in the presence of biomembranes: potential mechanisms of cell toxicity
Warmlander Sebastian K T S; Osterlund Nicklas; Wallin Cecilia; Jarvet Juri; Graslund Astrid; Wu Jinming; Luo Jinghui; Tiiman Ann; Jarvet Juri
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry (2019), 24 (8), 1189-1196 ISSN:.
The amyloid-β (Aβ) peptides are key molecules in Alzheimer's disease (AD) pathology. They interact with cellular membranes, and can bind metal ions outside the membrane. Certain oligomeric Aβ aggregates are known to induce membrane perturbations and the structure of these oligomers-and their membrane-perturbing effects-can be modulated by metal ion binding. If the bound metal ions are redox active, as e.g., Cu and Fe ions are, they will generate harmful reactive oxygen species (ROS) just outside the membrane surface. Thus, the membrane damage incurred by toxic Aβ oligomers is likely aggravated when redox-active metal ions are present. The combined interactions between Aβ oligomers, metal ions, and biomembranes may be responsible for at least some of the neuronal death in AD patients.
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Xu, S.; Wang, W.; Dong, X.; Sun, Y. Molecular Insight into Cu2+-Induced Conformational Transitions of Amyloid β-Protein from Fast Kinetic Analysis and Molecular Dynamics Simulations. ACS Chem. Neurosci. 2021, 12, 300– 310, DOI: 10.1021/acschemneuro.0c00502
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Molecular Insight into Cu2+-Induced Conformational Transitions of Amyloid β-Protein from Fast Kinetic Analysis and Molecular Dynamics Simulations
Xu, Shaoying; Wang, Wenjuan; Dong, Xiaoyan; Sun, Yan
ACS Chemical Neuroscience (2021), 12 (2), 300-310CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
Cu2+-mediated amyloid β-protein (Aβ) aggregation is implicated in the pathogenesis of Alzheimer's disease, so it is of significance to understand Cu2+-mediated conformational transitions of Aβ. Herein, four Aβ mutants were created by using the environment-sensitive cyanophenylalanine to resp. substitute F4, Y10, F19, and F20 residues of Aβ40. By using stopped-flow fluorescence spectroscopy and mol. dynamics (MD) simulations, the early stage conformational transitions of the mutants mediated by Cu2+ binding were studied. The fast kinetics unveils that Cu2+ has more significant influence on the conformational changes of N-terminal (F4 and Y10) than on the central hydrophobic core (CHC, F19, and F20) under different pH conditions (pH 6.6-8.0), esp. Y10. Lag periods of the conformational transitions are obsd. for the F19 and F20 mutants at pH 8.0, indicating the slow response of the two mutation sites on the conformational transitions. More importantly, significantly longer lag periods for F20 than for F19 indicate the conduction of the transition from F19 to F20. The conduction time (difference in lag period) decreases from 4.5 s at Cu2+ = 0 to undetectable (<1 ms) at Cu2+ = 10μM. The significant difference in the response time of F19 and F20 and the fast local conformational changes of Y10 imply that the conformational transitions of Aβ start around Y10. MD simulations support the observation of hydrophobicity increase at N-terminal during the conformational transitions of Aβ-Cu2+. It also reveals that Y10 is immediately approached by Cu2+, supporting the speculation that the starting point of conformational transitions of Aβ is near Y10. The work provided mol. insight into the early stage conformational transitions of Aβ40 mediated by Cu2+.
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Matsuzaki, K. Formation of Toxic Amyloid Fibrils by Amyloid β-Protein on Ganglioside Clusters. Int. J. Alzheimer’s Dis. 2011, 2011, 956104, DOI: 10.4061/2011/956104
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Formation of Toxic Amyloid Fibrils by Amyloid β-Protein on Ganglioside Clusters
Matsuzaki Katsumi
International journal of Alzheimer's disease (2011), 2011 (), 956104 ISSN:.
It is widely accepted that the conversion of the soluble, nontoxic amyloid β-protein (Aβ) monomer to aggregated toxic Aβ rich in β-sheet structures is central to the development of Alzheimer's disease. However, the mechanism of the abnormal aggregation of Aβ in vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβ aggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβ amyloids formed in solution. Furthermore, differences between Aβ-(1-40) and Aβ-(1-42) in membrane interaction and amyloidogenesis are also emphasized.
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Matsuzaki, K. Physicochemical Interactions of Amyloid Beta-Peptide with Lipid Bilayers. Biochim. Biophys. Acta 2007, 1768, 1935– 1942, DOI: 10.1016/j.bbamem.2007.02.009
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Physicochemical interactions of amyloid β-peptide with lipid bilayers
Matsuzaki, Katsumi
Biochimica et Biophysica Acta, Biomembranes (2007), 1768 (8), 1935-1942CODEN: BBBMBS; ISSN:0005-2736. (Elsevier Ltd.)
A review. The aggregation and deposition onto neuronal cells of amyloid β-peptide (Aβ) is central to the pathogenesis of Alzheimer's disease. Accumulating evidence suggests that membranes play a catalytic role in the aggregation of Aβ. This article summarizes the structures and properties of Aβ in soln. and the physicochem. interaction of Aβ with lipid bilayers of various compns. Reasons for discrepancies between results by different research groups are discussed. The importance of ganglioside clusters in the aggregation of Aβ is emphasized. Finally, a hypothetical physicochem. cascade in the pathogenesis of the disease is proposed.
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Matsuzaki, K.; Kato, K.; Yanagisawa, K. Abeta Polymerization through Interaction with Membrane Gangliosides. Biochim. Biophys. Acta 2010, 1801, 868– 877, DOI: 10.1016/j.bbalip.2010.01.008
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Aβ polymerization through interaction with membrane gangliosides
Matsuzaki, Katsumi; Kato, Koichi; Yanagisawa, Katsuhiko
Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2010), 1801 (8), 868-877CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
A review. Clarification of the mol. and cellular mechanisms underlying the assembly of amyloid β-protein (Aβ) into insol. fibrils in the brain has been one of the biggest challenges in the research on Alzheimer disease (AD). We previously identified a novel Aβ species, which was characterized by its tight binding to GM1 ganglioside (GM1), in the brain showing early pathol. changes of AD. The ganglioside-bound Aβ (GAβ) possessed unique characteristics, including its altered immunoreactivity, which suggests its distinct conformation from native Aβ, and its strong potency to accelerate Aβ assembly into fibrils. On the basis of these characteristics, it was hypothesized that Aβ adopts an altered conformation following interaction with GM1, leading to the generation of GAβ, and then GAβ acts as an endogenous seed for Alzheimer amyloid in the brain. To date, various in vitro and in vivo studies on GAβ have revealed how Aβ binds to gangliosides, i.e., what are the favorable physicochem. and neurobiol. conditions for generating GAβ, and what is the pathol. significance of ganglioside-induced Aβ assembly in the development of AD. Interestingly, GAβ is favorably generated in the unique ganglioside-enriched (clustered), raft-like microdomains; moreover, amyloid fibrils formed in the presence of gangliosides are neurotoxic. Furthermore, the conformational change of Aβ in the presence of ganglioside has been characterized by an NMR study. In this review, we focus on the recent progress of GAβ studies and highlight the possibility that ganglioside binding is the initial and common step in the development of a part of human misfolding-type amyloidosis, including AD.
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Okada, T.; Ikeda, K.; Wakabayashi, M.; Ogawa, M.; Matsuzaki, K. Formation of Toxic Abeta(1-40) Fibrils on GM1 Ganglioside-Containing Membranes Mimicking Lipid Rafts: Polymorphisms in Abeta(1-40) Fibrils. J. Mol. Biol. 2008, 382, 1066– 1074, DOI: 10.1016/j.jmb.2008.07.072
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Formation of Toxic Aβ(1-40) Fibrils on GM1 Ganglioside-Containing Membranes Mimicking Lipid Rafts: Polymorphisms in Aβ(1-40) Fibrils
Okada, Takuma; Ikeda, Keisuke; Wakabayashi, Masaki; Ogawa, Mariko; Matsuzaki, Katsumi
Journal of Molecular Biology (2008), 382 (4), 1066-1074CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)
The abnormal aggregation and deposition of amyloid β protein (Aβ) on neuronal cells are crit. to the onset of Alzheimer's disease. The entity (oligomers or fibrils) of toxic Aβ species responsible for the pathogenesis of the disease has been controversial. The authors have reported that the Aβ aggregates on ganglioside-rich domains of neuronal PC12 cells as well as in raft-like model membranes. Here, we identified toxic Aβ(1-40) aggregates formed with GM1-ganglioside-contg. membranes. Aβ(1-40) was incubated with raft-like liposomes composed of GM1/cholesterol/sphingomyelin at 1:2:2 and 37 °C. After a lag period, toxic amyloid fibrils with a width of 12 nm were formed and subsequently laterally assembled with slight changes in their secondary structure as confirmed by viability assay, thioflavin-T fluorescence, CD, and transmission electron microscopy. In striking contrast, Aβ fibrils formed without membranes were thinner (6.7 nm) and much less toxic because of weaker binding to cell membranes and a smaller surface hydrophobicity. This study suggests that toxic Aβ(1-40) species formed on membranes are not sol. oligomers but amyloid fibrils and that Aβ(1-40) fibrils exhibit polymorphisms.
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Ogawa, M.; Tsukuda, M.; Yamaguchi, T.; Ikeda, K.; Okada, T.; Yano, Y.; Hoshino, M.; Matsuzaki, K. Ganglioside-Mediated Aggregation of Amyloid β-Proteins (Aβ): Comparison between Aβ-(1-42) and Aβ-(1-40). J. Neurochem. 2011, 116, 851– 857, DOI: 10.1111/j.1471-4159.2010.06997.x
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Ganglioside-mediated aggregation of amyloid β-proteins (Aβ): comparison between Aβ-(1-42) and Aβ-(1-40)
Ogawa, Mariko; Tsukuda, Miho; Yamaguchi, Takahiro; Ikeda, Keisuke; Okada, Takuma; Yano, Yoshiaki; Hoshino, Masaru; Matsuzaki, Katsumi
Journal of Neurochemistry (2011), 116 (5), 851-857CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
Conversion of the sol., non-toxic amyloid β-protein (Aβ) into an aggregated, toxic form rich in β-sheets is considered a key step in the development of Alzheimer's disease. Accumulating evidence suggests that lipid rafts in membranes play a pivotal role in this process. We have proposed that Aβ-(1-40) specifically bound to a ganglioside cluster forms cytotoxic fibrils via a conformational transition from an α-helix-rich structure to a β-sheet-rich one. In the present study, we compared the interaction of Aβ-(1-40) and Aβ-(1-42) with both model and living cell membranes. Aβ-(1-42) exhibited lipid specificity and affinity similar to Aβ-(1-40), though its amyloidogenic activity was more than 10-fold that of Aβ-(1-40). Antibody staining expts., using the A11 antibody specific to Aβ oligomers, demonstrated that oligomers were not detected during the aggregation process, and cell death was obsd. only after significant accumulation of the proteins, suggesting that the fibril-induced disruption of cell membranes leads to the cytotoxicity. Furthermore, we succeeded in visualizing fibrils formed on cell membranes using total internal reflection fluorescence microscopy. Aβ-(1-40) formed long fibrils appeared to be laterally co-assembled and short.
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Chen, W.-T.; Liao, Y.-H.; Yu, H.-M.; Cheng, I. H.; Chen, Y.-R. Distinct Effects of Zn²⁺, Cu²⁺, Fe³⁺, and Al³⁺ on Amyloid-β Stability, Oligomerization, and Aggregation: AMYLOID-β DESTABILIZATION PROMOTES ANNULAR PROTOFIBRIL FORMATION *. J. Biol. Chem. 2011, 286, 9646– 9656, DOI: 10.1074/jbc.M110.177246
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Distinct Effects of Zn2+, Cu2+, Fe3+, and Al3+ on Amyloid-β Stability, Oligomerization, and Aggregation: Amyloid-β destabilization promotes annular protofibril formation
Chen, Wei-Ting; Liao, Yi-Hung; Yu, Hui-Ming; Cheng, Irene H.; Chen, Yun-Ru
Journal of Biological Chemistry (2011), 286 (11), 9646-9656CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
Abnormally high concns. of Zn2+, Cu2+, and Fe3+ are present along with amyloid-β (Aβ) in the senile plaques in Alzheimer disease, where Al3+ is also detected. Aβ aggregation is the key pathogenic event in Alzheimer disease, where Aβ oligomers are the major culprits. The fundamental mechanism of these metal ions on Aβ remains elusive. Here, we employ 4,4'-Bis(1-anilinonaphthalene 8-sulfonate) and tyrosine fluorescence, CD, stopped flow fluorescence, guanidine hydrochloride denaturation, and photo-induced crosslinking to elucidate the effect of Zn2+, Cu2+, Fe3+, and Al3+ on Aβ at the early stage of the aggregation. Furthermore, thioflavin T assay, dot blotting, and TEM are utilized to examine Aβ aggregation. Our results show that Al3+ and Zn2+, but not Cu2+ and Fe3+, induce larger hydrophobic exposures of Aβ conformation, resulting in its significant destabilization at the early stage. The metal ion binding induces Aβ conformational changes with micromolar binding affinities and millisecond binding kinetics. Cu2+ and Zn2+ induce similar assembly of transiently appearing Aβ oligomers at the early state. During the aggregation, we found that Zn2+ exclusively promotes the annular protofibril formation without undergoing a nucleation process, whereas Cu2+ and Fe3+ inhibit fibril formation by prolonging the nucleation phases. Al3+ also inhibits fibril formation; however, the annular oligomers co-exist in the aggregation pathway. In conclusion, Zn2+, Cu2+, Fe3+, and Al3+ adopt distinct folding and aggregation mechanisms to affect Aβ, where Aβ destabilization promotes annular protofibril formation. Our study facilitates the understanding of annular Aβ oligomer formation upon metal ion binding.
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Frederickson, C. J.; Koh, J.-Y.; Bush, A. I. The Neurobiology of Zinc in Health and Disease. Nat. Rev. Neurosci. 2005, 6, 449– 462, DOI: 10.1038/nrn1671
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The neurobiology of zinc in health and disease
Frederickson, Christopher J.; Koh, Jae-Young; Bush, Ashley I.
Nature Reviews Neuroscience (2005), 6 (6), 449-462CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)
A review. The use of zinc in medicinal skin creams was mentioned in Egyptian papyri from 2000 BC (for example, the Smith Papyrus), and zinc has apparently been used fairly steadily throughout Roman and modern times (for example, as the American lotion Calamine named for its zinc ore). It is somewhat ironic that zinc is a relatively late addn. to the pantheon of signal ions in biol. and medicine. The no. of Zn biol. functions, health implications, and emerging pharmacol. targets indicate that Zn might be 'the calcium of the 21st century'.
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Lovell, M. A.; Robertson, J. D.; Teesdale, W. J.; Campbell, J. L.; Markesbery, W. R. Copper, Iron and Zinc in Alzheimer’s Disease Senile Plaques. J. Neurol. Sci. 1998, 158, 47– 52, DOI: 10.1016/s0022-510x(98)00092-6
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Copper, iron and zinc in Alzheimer's disease senile plaques
Lovell, M. A.; Robertson, J. D.; Teesdale, W. J.; Campbell, J. L.; Markesbery, W. R.
Journal of the Neurological Sciences (1998), 158 (1), 47-52CODEN: JNSCAG; ISSN:0022-510X. (Elsevier Science B.V.)
Concns. of copper (Cu), iron (Fe) and zinc (Zn) were measured in the rims and cores of senile plaques (SP) and in the neuropil of the amygdala of nine Alzheimer's disease (AD) patients and in the neuropil of the amygdala of five neurol. normal control subjects using micro particle-induced X-ray emission (micro-PIXE). Comparison of SP rim and core values revealed no significant differences between levels of Cu, Fe or Zn. Zinc and Fe in SP rims and cores were significantly elevated in AD compared with AD neuropil (P<0.05). Copper was significantly elevated (P<0.05) in the rim of SP compared with AD neuropil. Comparison of AD and control neuropil revealed a significant (P<0.05) elevation of Zn in AD subjects. The elevation of these elements in SP in AD is of interest in light of the observation that Cu, Fe and particularly Zn, can accelerate aggregation of amyloid beta peptide.
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Somavarapu, A. K.; Shen, F.; Teilum, K.; Zhang, J.; Mossin, S.; Thulstrup, P. W.; Bjerrum, M. J.; Tiwari, M. K.; Szunyogh, D.; Søtofte, P. M.; Kepp, K. P.; Hemmingsen, L. The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+ −Aβ Complex. Chemistry 2017, 23, 13591– 13595, DOI: 10.1002/chem.201703440
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The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+-Aβ Complex
Somavarapu, Arun K.; Shen, Fei; Teilum, Kaare; Zhang, Jingdong; Mossin, Susanne; Thulstrup, Peter W.; Bjerrum, Morten J.; Tiwari, Manish K.; Szunyogh, Daniel; Sotofte, Peter M.; Kepp, Kasper P.; Hemmingsen, Lars
Chemistry - A European Journal (2017), 23 (55), 13591-13595CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
A prominent current hypothesis is that impaired metal ion homeostasis may contribute to Alzheimer's disease (AD). We elucidate the interaction of Cu2+ with wild-type (WT) Aβ1-40 and the genetic variants A2T and A2V which display increasing pathogenicity as A2T<WT<A2V. Cu2+ significantly extends the lag phase in aggregation kinetics, in particular for the pathogenic A2V variant. Addnl., a rapid, initial, low intensity ThT response is obsd., possibly reflecting formation of Cu2+ induced amorphous aggregates, as supported by at. force microscopy (AFM) and CD spectroscopy, again most notably for the A2V variant. ESR (EPR) spectroscopy gives pKa values for transition between two Cu2+ coordination geometries (component I and II) of 7.4 (A2T), 7.9 (WT), and 8.4 (A2V), i.e., component I is stabilized at physiol. pH in the order A2T < WT < A2V. 1H NMR relaxation exhibits the same trend for the non-coordinating arom. residues (A2T<WT<A2V), and implies markedly faster inter-peptide Cu2+ exchange for the A2V variant than for WT and A2T. We therefore hypothesize that component I of the Cu-Aβ complex is related to pathogenicity, accounting for both the pathogenic nature of the A2V variant and the protective nature of the A2T variant.
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Raman, B.; Ban, T.; Yamaguchi, K.-I.; Sakai, M.; Kawai, T.; Naiki, H.; Goto, Y. Metal Ion-Dependent Effects of Clioquinol on the Fibril Growth of an Amyloid β Peptide. J. Biol. Chem. 2005, 280, 16157– 16162, DOI: 10.1074/jbc.M500309200
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Metal ion-dependent effects of clioquinol on the fibril growth of an amyloid β peptide
Raman, Bakthisaran; Ban, Tadato; Yamaguchi, Kei-ichi; Sakai, Miyo; Kawai, Tomoji; Naiki, Hironobu; Goto, Yuji
Journal of Biological Chemistry (2005), 280 (16), 16157-16162CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
Although metal ions such as Cu2+, Zn2+, and Fe3+ are implicated to play a key role in Alzheimer's disease, their role is rather complex, and comprehensive understanding is not yet obtained. We show that Cu2+ and Zn2+ but not Fe3+ renders the amyloid β peptide, Aβ1-40, nonfibrillogenic in nature. However, preformed fibrils of Aβ1-40 were stable when treated with these metal ions. Consequently, fibril growth of Aβ1-40 could be switched on/off by switching the mol. between its apo- and holo-forms. Clioquinol, a potential drug for Alzheimer disease, induced resumption of the Cu2+-suppressed but not the Zn2+-suppressed fibril growth of Aβ1-40. The obsd. synergistic effect of clioquinol and Zn2+ suggests that Zn2+-clioquinol complex effectively retards fibril growth. Thus, clioquinol has dual effects; although it disaggregates the metal ion-induced aggregates of Aβ1-40 through metal chelation, it further retards the fibril growth along with Zn2+. These results indicate the mechanism of metal ions in suppressing Aβ amyloid formation, as well as providing information toward the use of metal ion chelators, particularly clioquinol, as potential drugs for Alzheimer's disease.
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Zhang, Y.; Rempel, D. L.; Zhang, J.; Sharma, A. K.; Mirica, L. M.; Gross, M. L. Pulsed Hydrogen–Deuterium Exchange Mass Spectrometry Probes Conformational Changes in Amyloid Beta (Aβ) Peptide Aggregation. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 14604– 14609, DOI: 10.1073/pnas.1309175110
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Pulsed hydrogen-deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aβ) peptide aggregation
Zhang, Ying; Rempel, Don L.; Zhang, Jun; Sharma, Anuj K.; Mirica, Liviu M.; Gross, Michael L.
Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (36), 14604-14609,S14604/1-S14604/6CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Probing the conformational changes of amyloid beta (Aβ) peptide aggregation is challenging, owing to the vast heterogeneity of the resulting sol. aggregates. To investigate the formation of these aggregates in soln., we designed a mass spectrometry (MS)-based biophys. approach and applied it to the formation of sol. aggregates of the Aβ42 peptide, the proposed causative agent in Alzheimer's disease. The approach incorporates pulsed hydrogen-deuterium exchange (HDX) coupled with MS anal. The combined approach provides evidence for a self-catalyzed aggregation with a lag phase, as obsd. previously by fluorescence methods. Unlike those approaches, pulsed hydrogen-deuterium exchange does not require modified Aβ42 (e.g., labeling with a fluorophore). Furthermore, the approach reveals that the center region of Aβ42 is first to aggregate, followed by the C and N termini. We also found that the lag phase in the aggregation of sol. species is affected by temp. and Cu2+ ions. This MS approach has sufficient structural resoln. to allow interrogation of Aβ aggregation in physiol. relevant environments. This platform should be generally useful for investigating the aggregation of other amyloid-forming proteins and neurotoxic sol. peptide aggregates.
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Dai, X.-L.; Sun, Y.-X.; Jiang, Z.-F. Cu(II) Potentiation of Alzheimer Abeta1-40 Cytotoxicity and Transition on Its Secondary Structure. Acta Biochim. Biophys. Sin. 2006, 38, 765– 772, DOI: 10.1111/j.1745-7270.2006.00228.x
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Cu(II) potentiation of Alzheimer Aβ1-40 cytotoxicity and transition on its secondary structure
Dai, Xue-Ling; Sun, Ya-Xuan; Jiang, Zhao-Feng
Acta Biochimica et Biophysica Sinica (2006), 38 (11), 765-772CODEN: ABBSC2; ISSN:1672-9145. (Blackwell Publishing Asia Pty Ltd.)
Mounting evidence has shown that dyshomeostasis of the redox-active biometals such as Cu and Fe can lead to oxidative stress, which plays a key role in the neuropathol. of Alzheimer's disease (AD). Here we demonstrate that with the formation of Cu(II)·Aβ1-40 complexes, copper markedly potentiates the neurotoxicity exhibited by β-amyloid peptide (Aβ). A greater amt. of hydrogen peroxide was released when Cu(II)·Aβ1-40 complexes was added to the xanthine oxidase/xanthine system detected by potassium iodide spectrophotometry. Copper bound to Aβ1-40 was obsd. by ESR (EPR) spectroscopy. CD studies indicated that copper chelation could cause a structural transition of Aβ. The addn. of copper to Aβ introduced an increase on β-sheet as well as α-helix, which may be responsible for the aggregation of Aβ. We hypothesized that Aβ aggregation induced by copper may be responsible for local injury in AD. The interaction between Cu2+ and Aβ also provides a possible mechanism for the enrichment of metal ions in amyloid plaques in the AD brain.
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Ha, C.; Ryu, J.; Park, C. B. Metal Ions Differentially Influence the Aggregation and Deposition of Alzheimer’s Beta-Amyloid on a Solid Template. Biochemistry 2007, 46, 6118– 6125, DOI: 10.1021/bi7000032
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Metal Ions Differentially Influence the Aggregation and Deposition of Alzheimer's β-Amyloid on a Solid Template
Ha, Chanki; Ryu, Jungki; Park, Chan Beum
Biochemistry (2007), 46 (20), 6118-6125CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
The abnormal deposition and aggregation of β-amyloid (Aβ) on brain tissues are considered to be one of the characteristic neuropathol. features of Alzheimer's disease (AD). Environmental conditions such as metal ions, pH, and cell membranes are assocd. with Aβ deposition and plaque formation. According to the amyloid cascade hypothesis of AD, the deposition of Aβ42 oligomers as diffuse plaques in vivo is an important earliest event, leading to the formation of fibrillar amyloid plaques by the further accumulation of sol. Aβ under certain environmental conditions. In order to characterize the effect of metal ions on amyloid deposition and plaque growth on a solid surface, we prepd. a synthetic template by immobilizing Aβ oligomers onto a N-hydroxysuccinimide ester-activated solid surface. According to our study using ex situ at. force microscopy (AFM), Fourier transform IR spectroscopy (FT-IR), and thioflavin T (ThT) fluorescence spectroscopy, Cu2+ and Zn2+ ions accelerated both Aβ40 and Aβ42 deposition but resulted only in the formation of "amorphous" aggregates. In contrast, Fe3+ induced the deposition of "fibrillar" amyloid plaques at neutral pH. Under mildly acidic environments, the formation of fibrillar amyloid plaques was not induced by any metal ion tested in this work. Using secondary ion mass spectroscopy (SIMS) anal., we found that binding Cu ions to Aβ deposits on a solid template occurred by the possible redn. of Cu ions during the interaction of Aβ with Cu2+. Our results may provide insights into the role of metal ions on the formation of fibrillar or amorphous amyloid plaques in AD.
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Greco, V.; Naletova, I.; Ahmed, I. M. M.; Vaccaro, S.; Messina, L.; La Mendola, D.; Bellia, F.; Sciuto, S.; Satriano, C.; Rizzarelli, E. Hyaluronan-Carnosine Conjugates Inhibit Aβ Aggregation and Toxicity. Sci. Rep. 2020, 10, 15998, DOI: 10.1038/s41598-020-72989-2
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Hyaluronan-carnosine conjugates inhibit Aβ aggregation and toxicity
Greco, Valentina; Naletova, Irina; Ahmed, Ikhlas M. M.; Vaccaro, Susanna; Messina, Luciano; La Mendola, Diego; Bellia, Francesco; Sciuto, Sebastiano; Satriano, Cristina; Rizzarelli, Enrico
Scientific Reports (2020), 10 (1), 15998CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
Alzheimer's disease is the most common neurodegenerative disorder. Finding a pharmacol. approach that cures and/or prevents the onset of this devastating disease represents an important challenge for researchers. According to the amyloid cascade hypothesis, increases in extracellular amyloid-β (Aβ) levels give rise to different aggregated species, such as protofibrils, fibrils and oligomers, with oligomers being the more toxic species for cells. Many efforts have recently been focused on multi-target ligands to address the multiple events that occur concurrently with toxic aggregation at the onset of the disease. Moreover, investigating the effect of endogenous compds. or a combination thereof is a promising approach to prevent the side effects of entirely synthetic drugs. In this work, we report the synthesis, structural characterization and Aβ antiaggregant ability of new derivs. of hyaluronic acid (Hy, 200 and 700 kDa) functionalized with carnosine (Car), a multi-functional natural dipeptide. The bioactive substances (HyCar) inhibit the formation of amyloid-type aggregates of Aβ42 more than the parent compds.; this effect is proportional to Car loading. Furthermore, the HyCar derivs. are able to dissolve the amyloid fibrils and to reduce Aβ-induced toxicity in vitro. The enzymic degrdn. of Aβ is also affected by the interaction with HyCar.
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Attanasio, F.; Convertino, M.; Magno, A.; Caflisch, A.; Corazza, A.; Haridas, H.; Esposito, G.; Cataldo, S.; Pignataro, B.; Milardi, D.; Rizzarelli, E. Carnosine Inhibits Aβ42 Aggregation by Perturbing the H-Bond Network in and around the Central Hydrophobic Cluster. ChemBioChem 2013, 14, 583– 592, DOI: 10.1002/cbic.201200704
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Carnosine Inhibits Aβ42 Aggregation by Perturbing the H-Bond Network in and around the Central Hydrophobic Cluster
Attanasio, Francesco; Convertino, Marino; Magno, Andrea; Caflisch, Amedeo; Corazza, Alessandra; Haridas, Haritha; Esposito, Gennaro; Cataldo, Sebastiano; Pignataro, Bruno; Milardi, Danilo; Rizzarelli, Enrico
ChemBioChem (2013), 14 (5), 583-592CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
Aggregation of the amyloid-β peptide (Aβ) into fibrillar structures is a hallmark of Alzheimer's disease. Thus, preventing self-assembly of the Aβ peptide is an attractive therapeutic strategy. Here, we used exptl. techniques and atomistic simulations to investigate the influence of carnosine, a dipeptide naturally occurring in the brain, on Aβ aggregation. Scanning force microscopy, CD and thioflavin T fluorescence expts. showed that carnosine does not modify the conformational features of Aβ42 but nonetheless inhibits amyloid growth. Mol. dynamics (MD) simulations indicated that carnosine interacts transiently with monomeric Aβ42 by salt bridges with charged side chains, and van der Waals contacts with residues in and around the central hydrophobic cluster (17LVFFA21). NMR expts. on the non-aggregative fragment Aβ12-28 did not evidence specific intermol. interactions between the peptide and carnosine, in agreement with MD simulations. However, a close inspection of the spectra revealed that carnosine interferes with the local propensity of the peptide to form backbone hydrogen bonds close to the central hydrophobic cluster (residues E22, S26 and N27). Finally, MD simulations of aggregation-prone Aβ heptapeptide segments show that carnosine reduces the propensity to form intermol. backbone hydrogen bonds in the region 18-24. Taken together, the exptl. and simulation results (cumulative MD sampling of 0.2 ms) suggest that, despite the inability of carnosine to form stable contacts with Aβ, it might block the pathway toward toxic aggregates by perturbing the hydrogen bond network near residues with key roles in fibrillogenesis.
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Wang, Q.; Liang, G.; Zhang, M.; Zhao, J.; Patel, K.; Yu, X.; Zhao, C.; Ding, B.; Zhang, G.; Zhou, F.; De Zheng, J. Novo Design of Self-Assembled Hexapeptides as β-Amyloid (Aβ) Peptide Inhibitors. ACS Chem. Neurosci. 2014, 5, 972– 981, DOI: 10.1021/cn500165s
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De Novo Design of Self-Assembled Hexapeptides as β-Amyloid (Aβ) Peptide Inhibitors
Wang, Qiuming; Liang, Guizhao; Zhang, Mingzhen; Zhao, Jun; Patel, Kunal; Yu, Xiang; Zhao, Chao; Ding, Binrong; Zhang, Ge; Zhou, Feimeng; Zheng, Jie
ACS Chemical Neuroscience (2014), 5 (10), 972-981CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
The ability of peptides to construct specific secondary structures provides a useful function for biomaterial design that cannot be achieved with traditional org. mols. and polymers. Inhibition of amyloid formation is a promising therapeutic approach for the treatment of neurodegenerative diseases. Existing peptide-based inhibitors are mainly derived from original amyloid sequences, which have very limited sequence diversity and activity. It is highly desirable to explore other peptide-based inhibitors that are not directly derived from amyloid sequences. Here, we develop a hybrid high-throughput computational method to efficiently screen and design hexapeptide inhibitors against amyloid-β (Aβ) aggregation and toxicity from the first principle. Computationally screened/designed inhibitors are then validated for their inhibition activity using biophys. expts. We propose and demonstrate a proof-of-concept of the "like-interacts-like" design principle that the self-assembling peptides are able to interact strongly with conformationally similar motifs of Aβ peptides and to competitively reduce Aβ-Aβ interactions, thus preventing Aβ aggregation and Aβ-induced toxicity. Such a de novo design can also be generally applicable to design new peptide inhibitors against other amyloid diseases, beyond traditional peptide inhibitors with homologous sequences to parent amyloid peptides.
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Barrera Guisasola, E. E.; Andujar, S. A.; Hubin, E.; Broersen, K.; Kraan, I. M.; Méndez, L.; Delpiccolo, C. M. L.; Masman, M. F.; Rodríguez, A. M.; Enriz, R. D. New Mimetic Peptides Inhibitors of Αβ Aggregation. Molecular Guidance for Rational Drug Design. Eur. J. Med. Chem. 2015, 95, 136– 152, DOI: 10.1016/j.ejmech.2015.03.042
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New mimetic peptides inhibitors of Αβ aggregation. Molecular guidance for rational drug design
Barrera Guisasola, Exequiel E.; Andujar, Sebastian A.; Hubin, Ellen; Broersen, Kerensa; Kraan, Ivonne M.; Mendez, Luciana; Delpiccolo, Carina M. L.; Masman, Marcelo F.; Rodriguez, Ana M.; Enriz, Ricardo D.
European Journal of Medicinal Chemistry (2015), 95 (), 136-152CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compds. were obtained based on a mol. modeling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and TEM revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compds. Dot blot anal. suggested a decrease of sol. oligomers strongly assocd. with cognitive decline in Alzheimer's disease. For the mol. dynamics simulations, the authors used an Aβ42 pentameric model where the compds. were docked using a blind docking technique. To analyze the dynamic behavior of the complexes, extensive mol. dynamics simulations were carried out in explicit water. The authors also measured parameters or descriptors that allowed us to quantify the effect of these compds. as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of the Aβ42 protofibril model were identified. Among others the authors obsd. the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. The results may be helpful in the structural identification and understanding of the min. structural requirements for these mols. and might provide a guide in the design of new aggregation modulating ligands.
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Ryan, P.; Patel, B.; Makwana, V.; Jadhav, H. R.; Kiefel, M.; Davey, A.; Reekie, T. A.; Rudrawar, S.; Kassiou, M. Peptides, Peptidomimetics, and Carbohydrate-Peptide Conjugates as Amyloidogenic Aggregation Inhibitors for Alzheimer’s Disease. ACS Chem. Neurosci. 2018, 9, 1530– 1551, DOI: 10.1021/acschemneuro.8b00185
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Peptides, Peptidomimetics, and Carbohydrate-Peptide Conjugates as Amyloidogenic Aggregation Inhibitors for Alzheimer's Disease
Ryan, Philip; Patel, Bhautikkumar; Makwana, Vivek; Jadhav, Hemant R.; Kiefel, Milton; Davey, Andrew; Reekie, Tristan A.; Rudrawar, Santosh; Kassiou, Michael
ACS Chemical Neuroscience (2018), 9 (7), 1530-1551CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder accounting for 60-80% of dementia cases. For many years, AD causality was attributed to amyloid-β (Aβ) aggregated species. Recently, multiple therapies that target Aβ aggregation have failed in clin. trials, since Aβ aggregation is found in AD and healthy patients. Attention has therefore shifted towards the aggregation of the peptide tau as a major driver of AD. Numerous inhibitors of tau-based pathol. have recently been developed. Diagnosis of AD has shifted from measuring late stage senile plaques to early-stage biomarkers, amyloid and tau monomers and oligomeric assemblies. Synthetic peptides and some deriv. structures are being explored for use as theranostic tools as they possess the capacity to both bind the biomarkers, and to inhibit their pathol. self-assembly. Several studies have demonstrated that O-linked glycan addn. can significantly alter amyloid aggregation kinetics. Furthermore, natural O-glycosylation of amyloid-forming proteins, including amyloid precursor protein (APP), tau and α-synuclein, promote alternative non-amyloidogenic processing pathways. As such, glycopeptides and related peptidomimetics are being investigated within the AD field. Here we review advancements made in the last five years, as well as the arrival of sugar-based derivs.
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Asadbegi, M.; Shamloo, A. Identification of a Novel Multifunctional Ligand for Simultaneous Inhibition of Amyloid-Beta (Aβ42) and Chelation of Zinc Metal Ion. ACS Chem. Neurosci. 2019, 10, 4619– 4632, DOI: 10.1021/acschemneuro.9b00468
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Identification of a Novel Multifunctional Ligand for Simultaneous Inhibition of Amyloid-Beta (Aβ42) and Chelation of Zinc Metal Ion
Asadbegi, Mohsen; Shamloo, Amir
ACS Chemical Neuroscience (2019), 10 (11), 4619-4632CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
Zinc binding to β-amyloid structure could promote amyloid-β aggregation, as well as reactive oxygen species (ROS) prodn., as suggested in many exptl. and theor. studies. Therefore, the introduction of multifunctional drugs, capable of chelating zinc metal ion and inhibiting Aβ aggregation, is a promising strategy in the development of AD treatment. The present study has evaluated the efficacy of a new bifunctional peptide drug using mol. docking and mol. dynamics (MD) simulations. This drug composes of two different domains: inhibitor domain, obtained from C-terminal hydrophobic region of Aβ and Zn2+ chelating domain, derived from rapeseed meal, merging with a linker. The multifunctionality of the ligand was evaluated using a comprehensive set of MD simulations spanning up to 3.2 μs including Aβ relaxation, ligand-Zn2+ bilateral interaction, and more importantly, ligand-Zn2+-Aβ42 trilateral interactions. Anal. of the results strongly indicated that the bifunctional ligand can chelate zinc metal ion and avoid Aβ aggregation simultaneously. The present study illustrated that the proposed ligand has considerable hydrophobic interactions and hydrogen bonding with the monomeric Aβ in the presence of zinc metal ion. Therefore, in light of these considerable interactions and contacts, the α-helical structure of Aβ have been enhanced, while preventing the β-sheet formation as well as protecting the α-helix native structure. Furthermore, the anal. of interactions between Aβ and ligand-zinc complex revealed that the zinc metal ion is coordinated to Met13, the ending residue of the ligand and merely one residue in Aβ. The results have approved the previous exptl. and theor. findings in the literature about Aβ interactions with zinc metal ion and also Aβ interactions with the first domain of the proposed ligand. Moreover, the current research has evaluated the chelation using MD simulation and linear interaction energy (LIE) method and the result has been satisfactorily verified with previous exptl. and theor. (DFT) studies.
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Stellato, F.; Fusco, Z.; Chiaraluce, R.; Consalvi, V.; Dinarelli, S.; Placidi, E.; Petrosino, M.; Rossi, G. C.; Minicozzi, V.; Morante, S. The Effect of β-Sheet Breaker Peptides on Metal Associated Amyloid-β Peptide Aggregation Process. Biophys. Chem. 2017, 229, 110– 114, DOI: 10.1016/j.bpc.2017.05.005
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The effect of β-sheet breaker peptides on metal associated Amyloid-β peptide aggregation process
Stellato, F.; Fusco, Z.; Chiaraluce, R.; Consalvi, V.; Dinarelli, S.; Placidi, E.; Petrosino, M.; Rossi, G. C.; Minicozzi, V.; Morante, S.
Biophysical Chemistry (2017), 229 (), 110-114CODEN: BICIAZ; ISSN:0301-4622. (Elsevier B.V.)
Far-UV CD expts. and Atomic Force Microscopy tomog. are employed to assess the impact of β-sheet breakers on the Aβ1-40 peptide aggregation process in the presence of Cu2+ or Zn2+ transition metals. In this work we focus on two specific 5-amino acids long β-sheet breakers, namely the LPFFD Soto peptide, already known in the literature, and the LPFFN peptide recently designed and studied by our team. We provide evidence that both β-sheet breakers are effective in reducing the Aβ1-40 aggregation propensity, even in the presence of metal ions.
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Jensen, M.; Canning, A.; Chiha, S.; Bouquerel, P.; Pedersen, J. T.; Østergaard, J.; Cuvillier, O.; Sasaki, I.; Hureau, C.; Faller, P. Inhibition of Cu-Amyloid-β by Using Bifunctional Peptides with β-Sheet Breaker and Chelator Moieties. Chem. – Eur. J. 2012, 18, 4836– 4839, DOI: 10.1002/chem.201103546
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Inhibition of Cu-Amyloid-β by using Bifunctional Peptides with β-Sheet Breaker and Chelator Moieties
Jensen, Madeleine; Canning, Anne; Chiha, Sabri; Bouquerel, Pierre; Pedersen, Jeppe Trudslev; Ostergaard, Jesper; Cuvillier, Olivier; Sasaki, Isabelle; Hureau, Christelle; Faller, Peter
Chemistry - A European Journal (2012), 18 (16), 4836-4839, S4836/1-S4836/4CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Herein, the authors present a dual approach to inhibit Aβ aggregation and ROS prodn. by combining two functions on a single peptide, i.e., the copper chelator and β-sheet breaker moieties. Inhibition of the formation of toxic Aβ aggregates (oligomers and others) and disruption of Cu-Aβ with subsequent redox-silencing of Cu have been considered promising strategies against Alzheimer's disease progression.
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Rajasekhar, K.; Madhu, C.; Govindaraju, T. Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity. ACS Chem. Neurosci. 2016, 7, 1300– 1310, DOI: 10.1021/acschemneuro.6b00175
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Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity
Rajasekhar, K.; Madhu, Chilakapati; Govindaraju, T.
ACS Chemical Neuroscience (2016), 7 (9), 1300-1310CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
Accumulation of amyloid beta (Aβ) peptide and its aggregates in the human brain is considered as one of the hallmarks of Alzheimer's disease (AD). The polymorphic oligomers and fully grown fibrillar aggregates of Aβ exhibit different levels of neuronal toxicity. Moreover, aggregation of Aβ in the presence of redox-active metal ions like Cu2+ is responsible for the addnl. trait of cellular toxicity induced by the generation of reactive oxygen species (ROS). Herein, a multifunctional peptidomimetic inhibitor (P6) has been presented, based on a naturally occurring metal chelating tripeptide (GHK) and the inhibitor of Aβ aggregation. It was shown by employing various biophys. studies that P6 interact with Aβ and prevent the formation of toxic Aβ forms like oligomeric species and fibrillar aggregates. Further, P6 successfully sequestered Cu2+ from the Aβ-Cu2+ complex and maintained it in a redox-dormant state to prevent the generation of ROS. P6 inhibited membrane disruption by Aβ oligomers and efficiently prevented DNA damage caused by the Aβ-Cu2+ complex. PC12 cells were rescued from multifaceted Aβ toxicity when treated with P6, and the amt. of ROS generated in cells was reduced. These attributes make P6 a potential therapeutic candidate to ameliorate the multifaceted Aβ toxicity in AD.
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Hu, X.; Zhang, Q.; Wang, W.; Yuan, Z.; Zhu, X.; Chen, B.; Chen, X. Tripeptide GGH as the Inhibitor of Copper-Amyloid-β-Mediated Redox Reaction and Toxicity. ACS Chem. Neurosci. 2016, 7, 1255– 1263, DOI: 10.1021/acschemneuro.6b00145
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Tripeptide GGH as the Inhibitor of Copper-Amyloid-β-Mediated Redox Reaction and Toxicity
Hu, Xiaoyu; Zhang, Qian; Wang, Wei; Yuan, Zhi; Zhu, Xushan; Chen, Bing; Chen, Xingyu
ACS Chemical Neuroscience (2016), 7 (9), 1255-1263CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
The Aβ complexes of some redox-active species, such as Cu, cause oxidative stress and induce severe toxicity by generating reactive oxygen species (ROS). Thus, Cu chelation therapy should be considered as a valuable strategy for the treatment of Alzheimer's disease (AD). However, more attention should be paid to the specific chelating ability of these chelating agents. Herein, a tripeptide GGH was used to selectively chelate the Cu2+ in Aβ-Cu complex in the presence of other metal ions (e.g., K+, Ca2+, Ni2+, Mg2+, and Zn2+) as shown by isothermal titrn. calorimetry results. GGH decreased the level of HO• radicals by preventing the formation of intermediate Cu(I) ion. Thus, the Cu species completely lost its catalytic activity at a superequimolar GGH/Cu(II) ratio (4:1) as obsd. by UV-visible spectroscopy, coumarin-3-carboxylic acid fluorescence, and BCA assay. Moreover, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay indicates that GGH increased PC-12 cell viability from 36% to 63%, and neurotoxicity partly triggered by ROS decreased. These results indicate potential development of peptide chelation therapy for AD treatment.
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Rajasekhar, K.; Samanta, S.; Bagoband, V.; Murugan, N. A.; Govindaraju, T. Antioxidant Berberine-Derivative Inhibits Multifaceted Amyloid Toxicity. iScience 2020, 23, 101005, DOI: 10.1016/j.isci.2020.101005
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Antioxidant Berberine-Derivative Inhibits Multifaceted Amyloid Toxicity
Rajasekhar, Kolla; Samanta, Sourav; Bagoband, Vardhaman; Murugan, N. Arul; Govindaraju, Thimmaiah
iScience (2020), 23 (4), 101005CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)
Multiple lines of evidence indicate that amyloid beta (Aβ) peptide is responsible for the pathol. devastation caused in Alzheimer's disease (AD). Aβ aggregation species predominantly contribute to multifaceted toxicity obsd. in neuronal cells including generation of reactive oxygen species (ROS), mitochondrial dysfunction, interfering with synaptic signaling, and activation of premature apoptosis. Herein, we report a natural product berberine-derived (Ber-D) multifunctional inhibitor to ameliorate in cellulo multifaceted toxicity of AD. The structural attributes of polyphenolic Ber-D have contributed to its efficient Cu chelation and arresting the redox cycle to prevent the generation of ROS and rescue biomacromols. from oxidative damage. Ber-D inhibits metal-dependent and -independent Aβ aggregation, which is supported by in silico studies. Ber-D treatment averts mitochondrial dysfunction and corresponding neuronal toxicity contributing to premature apoptosis. These key multifunctional attributes make Ber-D a potential therapeutic candidate to ameliorate multifaceted Aβ toxicity in AD.
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Kim, M.; Kang, J.; Lee, M.; Han, J.; Nam, G.; Tak, E.; Kim, M. S.; Lee, H. J.; Nam, E.; Park, J.; Oh, S. J.; Lee, J.-Y.; Lee, J.-Y.; Baik, M.-H.; Lim, M. H. Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia. J. Am. Chem. Soc. 2020, 142, 8183– 8193, DOI: 10.1021/jacs.9b13100
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Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia
Kim, Mingeun; Kang, Juhye; Lee, Misun; Han, Jiyeon; Nam, Geewoo; Tak, Eunyoung; Kim, Min Sun; Lee, Hyuck Jin; Nam, Eunju; Park, Jiyong; Oh, Soo Jin; Lee, Ji-Yoon; Lee, Joo-Yong; Baik, Mu-Hyun; Lim, Mi Hee
Journal of the American Chemical Society (2020), 142 (18), 8183-8193CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Multiple pathogenic elements, including reactive oxygen species, amyloidogenic proteins, and metal ions, are assocd. with the development of neurodegenerative disorders. We report minimalistic redox-based principles for prepg. compact arom. compds. by derivatizing the phenylene moiety with various functional groups. These mol. agents display enhanced reactivities against multiple targets such as free radicals, metal-free amyloid-β (Aβ), and metal-bound Aβ that are implicated in the most common form of dementia, Alzheimer's disease (AD). Mechanistic studies reveal that the redox properties of these reagents are essential for their function. Specifically, they engage in oxidative reactions with metal-free and metal-bound Aβ, leading to chem. modifications of the Aβ peptides to form covalent adducts that alter the aggregation of Aβ. Moreover, the administration of the most promising candidate significantly attenuates the amyloid pathol. in the brains of AD transgenic mice and improves their cognitive defects. Our studies demonstrate an efficient and effective redox-based strategy for incorporating multiple functions into simple mol. reagents.
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Samanta, S.; Rajasekhar, K.; Babagond, V.; Govindaraju, T. Small Molecule Inhibits Metal-Dependent and -Independent Multifaceted Toxicity of Alzheimer’s Disease. ACS Chem. Neurosci. 2019, 10, 3611– 3621, DOI: 10.1021/acschemneuro.9b00216
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Small Molecule Inhibits Metal-Dependent and -Independent Multifaceted Toxicity of Alzheimer's Disease
Samanta, Sourav; Rajasekhar, Kolla; Babagond, Vardhaman; Govindaraju, Thimmaiah
ACS Chemical Neuroscience (2019), 10 (8), 3611-3621CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
Alzheimer's disease (AD) is one of the most devastating forms of dementia, without reliable treatments to cure, delay the onset of or prevent the disease progression. The proposed toxic mechanisms of AD include amyloidogenesis of amyloid β (Aβ), metal ions dyshomeostasis, redox active metal-Aβ inclusion complex formation and generation of excessive reactive oxygen and nitrogen species (ROS and RNS). The imbalance in redox homeostasis cause oxidative stress, DNA damage, mitochondrial dysfunction and inflammation, which collectively become a major hurdle in the development of effective therapeutic agents for multifactorial AD. This necessitates the need for a multifunctional strategy to develop effective therapeutic agents to inhibit multifaceted toxicity. In this context, we report a rational design, synthesis and detailed study to identify a small mol. multifunctional modulator (MFM) inspired by the human origin tripeptide. The lead MFM 4 chelates and sequester metal ions, disrupt their redox cycles and prevent excessive ROS prodn. and oxidative stress, ameliorate oxidative DNA damage and mitochondrial dysfunction, and modulate Nrf2 protein signaling under oxidative stress condition by eliminating the toxic stress elements. The MFM 4 was found to inhibit metal-dependent and independent Aβ aggregation and qualified as a suitable candidate to inhibit Aβ-induced neuronal toxicity. The NMR spectroscopy study revealed mol.-level interactions of 4 with Aβ42, which explain the mechanism of aggregation inhibition. Furthermore, 4 effectively inhibited the inflammation as revealed by redn. in nitric oxide (NO) prodn. in LPS-activated glial cells. These key features make 4 a potential MFM platform to develop therapeutic agents for metal (Cu, Zn and Fe)-dependent and independent multifaceted Aβ toxicity of AD.
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Stavchanskii, V. V.; Tvorogova, T. V.; Botsina, A. Y.; Limborska, S. A.; Skvortsova, V. I.; Myasoedov, N. F.; Dergunova, L. V. Effect of Peptide Semax and Its C-Terminal Fragment PGP on Vegfa Gene Expression during Incomplete Global Cerebral Ischemia in Rats. Mol. Biol. 2013, 47, 406– 410, DOI: 10.1134/S0026893313030151
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Effect of peptide Semax and its C-terminal fragment PGP on Vegfa gene expression during incomplete global cerebral ischemia in rats
Stavchanskii, V. V.; Tvorogova, T. V.; Botsina, A. Yu.; Limborska, S. A.; Skvortsova, V. I.; Myasoedov, N. F.; Dergunova, L. V.
Molecular Biology (Moscow, Russian Federation, English Edition) (2013), 47 (3), 406-410CODEN: MOLBBJ; ISSN:0026-8933. (SP MAIK Nauka/Interperiodica)
Vascular endothelial growth factor (VEGF-A) is hypoxia-inducible signal glycoprotein. VEGF-A induces vascular endothelial cell proliferation, which leads to the reconstitution of the vascular network in brain regions damaged by ischemia. However, this protein is also involved in the processes of inflammation and edema in early stages of ischemia. The synthetic peptide Semax has neuroprotective and anti-inflammatory properties and is actively used in the treatment of cerebral ischemia. We have previously shown that Semax reduces vascular injury and activates the mRNA synthesis of neurotrophins and their receptors during global cerebral ischemia in rats. In this work, we studied the effect of Semax and its C-terminal Pro-Gly-Pro tripeptide on Vegfa mRNA expression in different regions of the rat brain after 0.5, 1, 2, 4, 8, 12 and 24 h, which is the irreversible occlusion of the common carotid arteries. It was shown that ischemia increases the levels of Vegfa mRNA in rat brains (4 h after occlusion in cerebellum, cerebral cortex, and hippocampus; 8 h after occlusion in the cortex and hippocampus; and 24 h after occlusion in the cortex). Treatment with Semax reduces the levels of Vegfa mRNA in the frontal cortex (4, 8 and 12 h after occlusion) and the hippocampus (2 and 4 h after occlusion). The effect of PGP on the Vegfa gene expression was almost negligible. It was shown that Semax prevents the activating effect of hypoxia on the expression of the Vegfa gene at early stages of global cerebral ischemia. In turn, an increase in the level of Vegfa mRNA in the hippocampus 24 h after occlusion and Semax administration apparently reflects the neuroprotective properties of the drug.
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Bashkatova, V. G.; Koshelev, V. B.; Fadyukova, O. E.; Alexeev, A. A.; Vanin, A. F.; Rayevsky, K. S.; Ashmarin, I. P.; Armstrong, D. M. Novel Synthetic Analogue of ACTH 4–10 (Semax) but Not Glycine Prevents the Enhanced Nitric Oxide Generation in Cerebral Cortex of Rats with Incomplete Global Ischemia. Brain Res. 2001, 894, 145– 149, DOI: 10.1016/S0006-8993(00)03324-2
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Novel synthetic analogue of ACTH 4-10 (Semax) but not glycine prevents the enhanced nitric oxide generation in cerebral cortex of rats with incomplete global ischemia
Bashkatova, V. G.; Koshelev, V. B.; Fadyukova, O. E.; Alexeev, A. A.; Vanin, A. F.; Rayevsky, K. S.; Ashmarin, I. P.; Armstrong, D. M.
Brain Research (2001), 894 (1), 145-149CODEN: BRREAP; ISSN:0006-8993. (Elsevier Science B.V.)
This work investigates whether nitric oxide prodn. and lipid peroxidn. contribute to the pathophysiol. of ischemia and whether glycine and a novel Russian compd., Semax are neuroprotective via a mechanism involving the regulation nitric oxide (NO) and lipid peroxidn. In brief, nitric oxide and indexes of lipid peroxidn. were elevated following global ischemia. While glycine proved ineffective in reducing NO levels or ameliorating the neurol. deficits following global ischemia, Semax proved to be highly effective in abating the rise in nitric oxide and restoring neurol. functioning.
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Potaman, V. N.; Antonova, L. V.; Dubynin, V. A.; Zaitzev, D. A.; Kamensky, A. A.; Myasoedov, N. F.; Nezavibatko, V. N. Entry of the Synthetic ACTH(4–10) Analogue into the Rat Brain Following Intravenous Injection. Neurosci. Lett. 1991, 127, 133– 136, DOI: 10.1016/0304-3940(91)90912-D
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Entry of the synthetic ACTH(4-10) analog into the rat brain following intravenous injection
Potaman, V. N.; Antonova, L. V.; Dubynin, V. A.; Zaitsev, D. A.; Kamenskii, A. A.; Myasoedov, N. F.; Nezavibat'ko, V. N.
Neuroscience Letters (1991), 127 (1), 133-6CODEN: NELED5; ISSN:0304-3940.
In view of known central effects of N-terminal ACTH fragments, a possibility of their entry into the brain was studied. Rat blood and brain exts. after i.v. injection of the tritiated synthetic ACTH(4-10) analog, Met-Glu-His-Phe-Gly-Pro, were subjected to an HPLC anal. At two time points the labeled peptide was detected in brain exts. The brain to blood ratios of peptide content in brain and blood were found to be significantly higher than those calcd. for a distribution of labeled bovine serum albumin in rat brain capillaries and blood. This strongly suggests that this peptide penetrates into the brain tissues, its quantity not exceeding 0.01% of dose injected. Peptide diffusion through the vascular epithelium of brain capillaries could account for the data obtained.
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Kolomin, T.; Shadrina, M.; Slominsky, P.; Limborska, S.; Myasoedov, N. A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides. Neurosci. Med. 2013, 04, 720– 252, DOI: 10.4236/nm.2013.44035
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Storozhevykh, T. P.; Tukhbatova, G. R.; Senilova, Y. E.; Pinelis, V. G.; Andreeva, L. A.; Myasoyedov, N. F. Effects of Semax and Its Pro-Gly-Pro Fragment on Calcium Homeostasis of Neurons and Their Survival under Conditions of Glutamate Toxicity. Bull. Exp. Biol. Med. 2007, 143, 601– 604, DOI: 10.1007/s10517-007-0192-x
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Effects of semax and its Pro-Gly-Pro fragment on calcium homeostasis of neurons and their survival under conditions of glutamate toxicity
Storozhevykh, T. P.; Tukhbatova, G. R.; Senilova, Ya. E.; Pinelis, V. G.; Andreeva, L. A.; Myasoyedov, N. F.
Bulletin of Experimental Biology and Medicine (2007), 143 (5), 601-604CODEN: BEXBAN; ISSN:0007-4888. (Springer)
Semax (100 μM) and its Pro-Gly-Pro fragment (20 and 100 μM) delayed the development of calcium dysregulation and redn. of the mitochondrial potential in cultured cerebellar granule cells under conditions of glutamate neurotoxicity. Incubation with these peptides improved neuronal survival by on av. 30%. The neuroprotective effect of semax in cerebral ischemia/hypoxia can be due to improvement of mitochondrial resistance to "calcium" stress.
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Ashmarin, I. P.; Nezavibatko, V. N.; Levitskaya, N. G.; Koshelev, V. B.; Kamensky, A. A. Design and Investigation of an ACTH(4-10) Analogue Lacking D-Amino Acids and Hydrophobic Radicals. Neurosci. Res. Commun. 1995, 16, 105– 112
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Design and investigation of an ACTH(4-10) analog-lacking D-amino acids and hydrophobic radicals
Ashmarin, I. P.; Nezavibatko, V. N.; Levitskaya, N. G.; Koshelev, V. B.; Kamensky, A. A.
Neuroscience Research Communications (1995), 16 (2), 105-12CODEN: NRCOEE; ISSN:0893-6609.
The biol. activity of an ACTH(4-10) analog, Semax (MEHFPGP), has been studied. This peptide was shown to have a beneficial effect on the functions of the central nervous system. Semax accelerated the learning process in animals and had a prolonged effect in comparison to ACTH(4-10). It increased the resistance of rats exposed to hypobaric and circulatory hypoxia. Semax had a protective effect against the development of hemorrhagic stroke in rats. The data obtained underscore the potential of Semax as a stimulator of memory and mental functions and as a potential antihypoxic and antistroke drug.
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Kaplan, A. Y.; Kochetova, A. G.; Nezavibathko, V. N.; Rjasina, T. V.; Ashmarin, I. P. Synthetic ACTH Analogue Semax Displays Nootropic-like Activity in Humans. Neurosci. Res. Commun. 1996, 19, 115– 123, DOI: 10.1002/(SICI)1520-6769(199609)19:2<115::AID-NRC171>3.0.CO;2-B
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Synthetic ACTH analog Semax displays nootropic-like activity in humans
Kaplan, A. Ya.; Kochetova, A. G.; Nezavibathko, V. N.; Rjasina, T. V.; Ashmarion, I. P.
Neuroscience Research Communications (1996), 19 (2), 115-123CODEN: NRCOEE; ISSN:0893-6609. (Wiley)
Nootropic properties of the ACTH(4-10) analog Semax were demonstrated in expts. with human volunteers. The antihypoxic effect of Semax was shown by EEG anal. after short-term hyperventilation. Semax induced changes in the EEG similar to those seen after administration of typical nootropic drugs. Particularly important was the long-term (20-24 h) beneficial action of Semax on the work efficiency of operators after intranasal administration of 0.25-1.0 mg of the peptide (about 4.0-16.0 μg/kg body wt.).
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Dolotov, O. V.; Karpenko, E. A.; Seredenina, T. S.; Inozemtseva, L. S.; Levitskaya, N. G.; Zolotarev, Y. A.; Kamensky, A. A.; Grivennikov, I. A.; Engele, J.; Myasoedov, N. F. Semax, an Analogue of Adrenocorticotropin (4–10), Binds Specifically and Increases Levels of Brain-Derived Neurotrophic Factor Protein in Rat Basal Forebrain. J. Neurochem. 2006, 97, 82– 86, DOI: 10.1111/j.1471-4159.2006.03658.x
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Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain
Dolotov, Oleg V.; Karpenko, Ekaterina A.; Seredenina, Tamara S.; Inozemtseva, Lyudmila S.; Levitskaya, Natalia G.; Zolotarev, Yuriy A.; Kamensky, Andrey A.; Grivennikov, Igor A.; Engele, Juergen; Myasoedov, Nikolay F.
Journal of Neurochemistry (2006), 97 (Suppl. 1), 82-86CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)
The heptapeptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) is an analog of the N-terminal fragment (4-10) of adrenocorticotropic hormone which, after intranasal application, has profound effects on learning and memory formation in rodents and humans, and also exerts marked neuroprotective effects. A clue to the mol. mechanism underlying this neurotropic action was recently given by the observation that Semax stimulates the synthesis of brain-derived neurotrophic factor (BDNF), a potent modulator of synaptic plasticity, in astrocytes cultured from rat basal forebrain. In the present study, the authors investigated whether Semax affects BDNF levels in rat basal forebrain upon intranasal application of the peptide. In addn., the authors examd. whether cell membranes isolated from this brain region contained binding sites for Semax. The binding of tritium-labeled Semax was found to be time dependent, specific and reversible. Specific Semax binding required calcium ions and was characterized by a mean ± SEM dissocn. const. (KD) of 2.4±1.0 nM and a BMAX value of 33.5±7.9 fmol/mg protein. Sandwich immunoenzymic anal. revealed that Semax applied intranasally at 50 and 250 μg/kg bodyweight resulted in a rapid increase in BDNF levels after 3 h in the basal forebrain, but not in the cerebellum. These results point to the presence of specific binding sites for Semax in the rat basal forebrain. In addn., these findings indicate that the cognitive effects exerted by Semax might be assocd., at least in part, with increased BDNF protein levels in this brain region.
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Dolotov, O. V.; Karpenko, E. A.; Inozemtseva, L. S.; Seredenina, T. S.; Levitskaya, N. G.; Rozyczka, J.; Dubynina, E. V.; Novosadova, E. V.; Andreeva, L. A.; Alfeeva, L. Y.; Kamensky, A. A.; Grivennikov, I. A.; Myasoedov, N. F.; Engele, J. Semax, an Analog of ACTH(4–10) with Cognitive Effects, Regulates BDNF and TrkB Expression in the Rat Hippocampus. Brain Res. 2006, 1117, 54– 60, DOI: 10.1016/j.brainres.2006.07.108
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Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus
Dolotov, Oleg V.; Karpenko, Ekaterina A.; Inozemtseva, Lyudmila S.; Seredenina, Tamara S.; Levitskaya, Natalia G.; Rozyczka, Joanna; Dubynina, Elena V.; Novosadova, Ekaterina V.; Andreeva, Lyudmila A.; Alfeeva, Lyudmila Yu.; Kamensky, Andrey A.; Grivennikov, Igor A.; Myasoedov, Nikolay F.; Engele, Juergen
Brain Research (2006), 1117 (1), 54-60CODEN: BRREAP; ISSN:0006-8993. (Elsevier Ltd.)
The heptapeptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) is an analog of the ACTH fragment (4-10) which after intranasal application has profound effects on learning and exerts marked neuroprotective activities. Here, we found that a single application of Semax (50 μg/kg body wt.) results in a maximal 1.4-fold increase of BDNF protein levels accompanying with 1.6-fold increase of trkB tyrosine phosphorylation levels, and a 3-fold and a 2-fold increase of exon III BDNF and trkB mRNA levels, resp., in the rat hippocampus. Semax-treated animals showed a distinct increase in the no. of conditioned avoidance reactions. We suggest that Semax affects cognitive brain functions by modulating the expression and the activation of the hippocampal BDNF/trkB system.
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Tabbì, G.; Magrì, A.; Giuffrida, A.; Lanza, V.; Pappalardo, G.; Naletova, I.; Nicoletti, V. G.; Attanasio, F.; Rizzarelli, E. Semax, an ACTH4-10 Peptide Analog with High Affinity for Copper(II) Ion and Protective Ability against Metal Induced Cell Toxicity. J. Inorg. Biochem. 2015, 142, 39– 46, DOI: 10.1016/j.jinorgbio.2014.09.008
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Semax, an ACTH4-10 peptide analog with high affinity for copper(II) ion and protective ability against metal induced cell toxicity
Tabbi, Giovanni; Magri, Antonio; Giuffrida, Alessandro; Lanza, Valeria; Pappalardo, Giuseppe; Naletova, Irina; Nicoletti, Vincenzo Giuseppe; Attanasio, Francesco; Rizzarelli, Enrico
Journal of Inorganic Biochemistry (2015), 142 (), 39-46CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
Heptapeptide Semax, encompassing the sequence 4-7 of N-terminal domain of the adrenocorticotropic hormone (ACTH) and a C-terminal Pro-Gly-Pro tripeptide, belongs to a short regulatory peptides family. This compd. has been found to affect learning processes and to exert marked neuroprotective activities on cognitive brain functions. Dys-homeostasis of metal ions is involved in several neurodegenerative disorders and growing evidences have showed that brain is a specialized organ able to conc. metal ions. In this work, the metal binding ability and protective activity of Semax and its metal complexes were studied. The equil. study clearly demonstrated the presence of three complex species. Two minor species [CuL] and [CuLH-1]- co-exist together with the [CuLH-2]2- in the pH range from 3.6 to 5. From pH 5 the [CuLH-2]2- species becomes predominant with the donor atoms around copper arranged in a 4 N planar coordination mode. Noteworthy, a reduced copper induced cytotoxicity was obsd. in the presence of Semax by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay on a SHSY5Y neuroblastoma and RBE4 endothelial cell lines.
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Magrì, A.; Tabbì, G.; Giuffrida, A.; Pappalardo, G.; Satriano, C.; Naletova, I.; Nicoletti, V. G.; Attanasio, F. Influence of the N-Terminus Acetylation of Semax, a Synthetic Analog of ACTH(4-10), on Copper(II) and Zinc(II) Coordination and Biological Properties. J. Inorg. Biochem. 2016, 164, 59– 69, DOI: 10.1016/j.jinorgbio.2016.08.013
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Influence of the N-terminus acetylation of Semax, a synthetic analog of ACTH(4-10), on copper(II) and zinc(II) coordination and biological properties
Magri, Antonio; Tabbi, Giovanni; Giuffrida, Alessandro; Pappalardo, Giuseppe; Satriano, Cristina; Naletova, Irina; Nicoletti, Vincenzo G.; Attanasio, Francesco
Journal of Inorganic Biochemistry (2016), 164 (), 59-69CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
Semax is a heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro) that encompasses the sequence 4-7 of N-terminal domain of the adrenocorticotropic hormone and a C-terminal Pro-Gly-Pro tripeptide. N-terminal amino group acetylation (Ac-Semax) modulates the chem. and biol. properties of parental peptide, modifying the ability of Semax to form complex species with Cu(II) ion. At physiol. pH, the main complex species formed by Ac-Semax, [CuLH-2]2-, consists in a distorted CuN3O chromophore with a weak apical interaction of the methionine sulfur. Such a complex differs from the Cu(II)-Semax complex system, which exhibits a CuN4 chromophore. The reduced ligand field affects the [CuLH-2]2- formal redox potential, which is more pos. than that of Cu(II)-Semax corresponding species. In the amino-free form, the resulting complex species is redox-stable and unreactive against ascorbic acid, unlike the acetylated form. Semax acetylation did not protect from Cu(II) induced toxicity on a SH-SY5Y neuroblastoma cell line, thus demonstrating the crucial role played by the free NH2 terminus in the cell protection. Since several brain diseases are assocd. either to Cu(II) or Zn(II) dyshomeostasis, here we characterized also the complex species formed by Zn(II) with Semax and Ac-Semax. Both peptides were able to form Zn(II) complex species with comparable strength. Confocal microscopy imaging confirmed that peptide group acetylation does not affect the Zn(II) influx in neuroblastoma cells. Moreover, a punctuate distribution of Zn(II) within the cells suggests a preferred subcellular localization that might explain the zinc toxic effect. A future perspective can be the use of Ac-Semax as ionophore in antibody drug conjugates to produce a dysmetallostasis in tumor cells.
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Gade Malmos, K.; Blancas-Mejia, L. M.; Weber, B.; Buchner, J.; Ramirez-Alvarado, M.; Naiki, H.; Otzen, D. ThT 101: A Primer on the Use of Thioflavin T to Investigate Amyloid Formation. Amyloid 2017, 24, 1– 16, DOI: 10.1080/13506129.2017.1304905
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ThT 101: a primer on the use of thioflavin T to investigate amyloid formation
Gade Malmos, Kirsten; Blancas-Mejia, Luis M.; Weber, Benedikt; Buchner, Johannes; Ramirez-Alvarado, Marina; Naiki, Hironobu; Otzen, Daniel
Amyloid (2017), 24 (1), 1-16CODEN: AIJIET; ISSN:1350-6129. (Taylor & Francis Ltd.)
Thioflavin T (ThT) has been widely used to investigate amyloid formation since 1989. While concerns have recently been raised about its use as a probe specific for amyloid, ThT still continues to be a very valuable tool for studying kinetic aspects of fibrillation and assocd. inhibition mechanisms. This review aims to provide a conceptual instruction manual, covering appropriate considerations and pitfalls related to the use of ThT. We start by giving a brief introduction to amyloid formation with focus on the morphol. of different aggregate species, followed by a discussion of the quality of protein needed to obtain reliable fibrillation data. After an overview of the photochem. basis for ThT's amyloid binding properties and artifacts that may arise from this, we describe how to plan and analyze ThT assays. We conclude with recommendations for complementary techniques to address shortcomings in the ThT assay.
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Dorlet, P.; Gambarelli, S.; Faller, P.; Hureau, C. Pulse EPR Spectroscopy Reveals the Coordination Sphere of Copper(II) Ions in the 1–16 Amyloid-β Peptide: A Key Role of the First Two N-Terminus Residues. Angew. Chem., Int. Ed. 2009, 48, 9273– 9276, DOI: 10.1002/anie.200904567
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Pulse EPR Spectroscopy Reveals the Coordination Sphere of Copper(II) Ions in the 1-16 Amyloid-β Peptide: A Key Role of the First Two N-Terminus Residues
Dorlet, Pierre; Gambarelli, Serge; Faller, Peter; Hureau, Christelle
Angewandte Chemie, International Edition (2009), 48 (49), 9273-9276, S9273/1-S9273/14CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The authors used a wide range of EPR methods, including continuous wave, ESEEM, 4-pulse HYSCORE, and pulse ENDOR and 6-pulse HYSCORE, combined with specific isotopic labeling to study CuII-Aβ1-16 (DAEFRHDSGYEVHHQK). The unambiguous identification of the CuII ligands in components I and II achieved in this study underlines the key role of residues D1 and A2 in the coordination of the metal ion.
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Sarell, C. J.; Syme, C. D.; Rigby, S. E. J.; Viles, J. H. Copper(II) Binding to Amyloid-β Fibrils of Alzheimer’s Disease Reveals a Picomolar Affinity: Stoichiometry and Coordination Geometry Are Independent of Aβ Oligomeric Form. Biochemistry 2009, 48, 4388– 4402, DOI: 10.1021/bi900254n
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Copper(II) Binding to Amyloid-β Fibrils of Alzheimer's Disease Reveals a Picomolar Affinity: Stoichiometry and Coordination Geometry Are Independent of Aβ Oligomeric Form
Sarell, Claire J.; Syme, Christopher D.; Rigby, Stephen E. J.; Viles, John H.
Biochemistry (2009), 48 (20), 4388-4402CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
Cu2+ ions are found concd. within senile plaques of Alzheimer's disease patients directly bound to amyloid-β peptide (Aβ) and are linked to the neurotoxicity and self-assocn. of Aβ. The affinity of Cu2+ for monomeric Aβ is highly disputed, and there have been no reports of affinity of Cu2+ for fibrillar Aβ. We therefore measured the affinity of Cu2+ for both monomeric and fibrillar Aβ(1-42) using two independent methods: fluorescence quenching and CD. The binding curves were almost identical for both fibrillar and monomeric forms. Competition studies with free glycine, L-histidine, and nitrilotriacetic acid (NTA) indicate an apparent (conditional) dissocn. const. of 10-11 M, at pH 7.4. Previous studies of Cu-Aβ have typically found the affinity 2 or more orders of magnitude weaker, largely because the affinity of competing ligands or buffers has been underestimated. Aβ fibers are able to bind a full stoichiometric complement of Cu2+ ions with little change in their secondary structure and have coordination geometry identical to that of monomeric Aβ. ESR studies (EPR) with Aβ His/Ala analogs suggest a dynamic view of the tetragonal Cu2+ complex, with axial as well as equatorial coordination of imidazole nitrogens creating an ensemble of coordination geometries in exchange between each other. Furthermore, the N-terminal amino group is essential for the formation of high-pH complex II. The Aβ(1-28) fragment binds an addnl. Cu2+ ion compared to full-length Aβ, with appreciable affinity. This second binding site is revealed in Aβ(1-42) upon addn. of methanol, indicating hydrophobic interactions block the formation of this weaker carboxylate-rich complex. A Cu2+ affinity for Aβ of 1011 M-1 supports a modified amyloid cascade hypothesis in which Cu2+ is central to Aβ neurotoxicity.
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Faller, P.; Hureau, C.; Berthoumieu, O. Role of Metal Ions in the Self-Assembly of the Alzheimer’s Amyloid-β Peptide. Inorg. Chem. 2013, 52, 12193– 12206, DOI: 10.1021/ic4003059
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Role of Metal Ions in the Self-assembly of the Alzheimer's Amyloid-β Peptide
Faller, Peter; Hureau, Christelle; Berthoumieu, Olivia
Inorganic Chemistry (2013), 52 (21), 12193-12206CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
A review. Aggregation of amyloid-β (Aβ) by self-assembly into oligomers or amyloids is a central event in Alzheimer's disease. Coordination of transition-metal ions, mainly copper and zinc, to Aβ occurs in vivo and modulates the aggregation process. A survey of the impact of CuII and ZnII on the aggregation of Aβ reveals some general trends: (i) ZnII and CuII at high micromolar concns. and/or in a large superstoichiometric ratio compared to Aβ have a tendency to promote amorphous aggregations (pptn.) over the ordered formation of fibrillar amyloids by self-assembly; (ii) metal ions affect the kinetics of Aβ aggregations, with the most significant impact on the nucleation phase; (iii) the impact is metal-specific; (iv) CuII and ZnII affect the concns. and/or the types of aggregation intermediates formed; (v) the binding of metal ions changes both the structure and the charge of Aβ. The decrease in the overall charge at physiol. pH increases the overall driving force for aggregation but may favor more pptn. over fibrillation, whereas the induced structural changes seem more relevant for the amyloid formation.
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Sarell, C. J.; Wilkinson, S. R.; Viles, J. H. Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease. J. Biol. Chem. 2010, 285, 41533– 41540, DOI: 10.1074/jbc.M110.171355
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Substoichiometric levels of Cu2+ ions Accelerate the kinetics of fiber formation and promote cell toxicity of amyloid-β from Alzheimer disease
Sarell, Claire J.; Wilkinson, Shane R.; Viles, John H.
Journal of Biological Chemistry (2010), 285 (53), 41533-41540CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
A role for Cu2+ ions in Alzheimer disease is often disputed, as it is believed that Cu2+ ions only promote nontoxic amorphous aggregates of amyloid-β (Aβ). In contrast with currently held opinion, we show that the presence of substoichiometric levels of Cu2+ ions in fact doubles the rate of prodn. of amyloid fibers, accelerating both the nucleation and elongation of fiber formation. We suggest that binding of Cu2+ ions at a physiol. pH causes Aβ to approach its isoelec. point, thus inducing self-assocn. and fiber formation. We further show that Cu2+ ions bound to Aβ are consistently more toxic to neuronal cells than Aβ in the absence of Cu2+ ions, whereas Cu2+ ions in the absence of Aβ are not cytotoxic. The degree of Cu-Aβ cytotoxicity correlates with the levels of Cu2+ ions that accelerate fiber formation. We note the effect appears to be specific for Cu2+ ions as Zn2+ ions inhibit the formation of fibers. An active role for Cu2+ ions in accelerating fiber formation and promoting cell death suggests impaired copper homeostasis may be a risk factor in Alzheimer disease.
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Zhang, Q.; Hu, X.; Wang, W.; Yuan, Z. Study of a Bifunctional Aβ Aggregation Inhibitor with the Abilities of Antiamyloid-β and Copper Chelation. Biomacromolecules 2016, 17, 661– 668, DOI: 10.1021/acs.biomac.5b01603
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Study of a Bifunctional Aβ Aggregation Inhibitor with the Abilities of Antiamyloid-β and Copper Chelation
Zhang, Qian; Hu, Xiaoyu; Wang, Wei; Yuan, Zhi
Biomacromolecules (2016), 17 (2), 661-668CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
In this study, a bifunctional Aβ aggregation inhibitor peptide, GGHRYYAAFFARR (GR), with the abilities to bind copper and antiamyloid was designed to inhibit the neurotoxicity of the Aβ-Cu(II) complex. The thioflavin T (ThT) assay, turbidimetric anal., transmission electron microscopy (TEM), and (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay were used to study its potential inhibitory effect on Aβ aggregation. Our findings indicate that GGH was the specific chelating sequence and that the RYYAAFFARR (RR) component acted as an aggregation inhibitor. More importantly, GR significantly decreased the cytotoxicity of the Aβ-Cu(II) complex. The cell viability improved to 88%, which was higher than with the single functional peptide GGH and RR by 39% and 20%, resp. Moreover, the qual. effect of Cu(II) on the Aβ-Cu(II) complex was also studied. Our results indicate that Cu(II) induces the formation of the β-sheet structure with a subequimolar Cu(II):Aβ molar ratio (0.25:1) but led to increased ROS prodn. at a supra-equimolar ratio.
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Faller, P.; Hureau, C. Bioinorganic Chemistry of Copper and Zinc Ions Coordinated to Amyloid-β Peptide. Dalton Trans. 2009, 7, 1080– 1094, DOI: 10.1039/B813398K
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Tõugu, V.; Karafin, A.; Palumaa, P. Binding of Zinc(II) and Copper(II) to the Full-Length Alzheimer’s Amyloid-Beta Peptide. J. Neurochem. 2008, 104, 1249– 1259, DOI: 10.1111/j.1471-4159.2007.05061.x
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Binding of zinc(II) and copper(II) to the full-length Alzheimer's amyloid-β peptide
Tougu, Vello; Karafin, Ann; Palumaa, Peep
Journal of Neurochemistry (2008), 104 (5), 1249-1259CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)
There is evidence that binding of metal ions like Zn2+ and Cu2+ to amyloid beta-peptides (Aβ) may contribute to the pathogenesis of Alzheimer's disease (AD). Cu2+ and Zn2+ form complexes with Aβ peptides in vitro; however, the published metal-binding affinities of Aβ vary in an enormously large range. We studied the interactions of Cu2+ and Zn2+ with monomeric Aβ40 under different conditions using intrinsic Aβ fluorescence and metal-selective fluorescent dyes. We showed that Cu2+ forms a stable and sol. 1: 1 complex with Aβ40; however, buffer compds. act as competitive copper-binding ligands and affect the apparent KD. Buffer-independent conditional KD for Cu(II)-Aβ40 complex at pH 7.4 is equal to 0.035 μmol/L. Interaction of Aβ40 with Zn2+ is more complicated, as partial aggregation of the peptide occurs during zinc titrn. expt. and in the same time period (within 30 min) the initial Zn-Aβ40 complex (KD = 60 μmol/L) undergoes a transition to a more tight complex with KD ∼ 2 μmol/L. Competition of Aβ40 with ion-selective fluorescent dyes Phen Green and Zincon showed that the KD values detd. from intrinsic fluorescence of Aβ correspond to the binding of the first Cu2+ and Zn2+ ions to the peptide with the highest affinity. Interaction of both Zn2+ and Cu2+ ions with Aβ peptides may occur in brain areas affected by Alzheimer's disease and Zn2+-induced transition in the peptide structure might contribute to amyloid plaque formation.
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Alies, B.; Renaglia, E.; Rózga, M.; Bal, W.; Faller, P.; Hureau, C. Cu(II) Affinity for the Alzheimer’s Peptide: Tyrosine Fluorescence Studies Revisited. Anal. Chem. 2013, 85, 1501– 1508, DOI: 10.1021/ac302629u
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Cu(II) Affinity for the Alzheimer's Peptide: Tyrosine Fluorescence Studies Revisited
Alies, Bruno; Renaglia, Emelyne; Rozga, Malgorzata; Bal, Wojciech; Faller, Peter; Hureau, Christelle
Analytical Chemistry (Washington, DC, United States) (2013), 85 (3), 1501-1508CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
Copper(II) binding to the amyloid-β peptide has been proposed to be a key event in the cascade leading to Alzheimer's disease. As a direct consequence, the strength of the Cu(II) to Aβ interaction, i.e., the Cu(II) affinity of Aβ, is a very important parameter to det. Because Aβ peptide contain one Tyr fluorophore in its sequence and because Cu(II) does quench Tyr fluorescence, fluorescence measurements appear to be a straightforward way to obtain this parameter. However, this proved to be wrong, mainly because of data misinterpretation in some previous studies that lead to a conflicting situation. In the present paper, we have investigated in details a large set of fluorescence data that were analyzed with a new method taking into account the presence of two Cu(II) sites and the inner-filter effect. This leads to reinterpretation of the published data and to the detn. of a unified affinity value in the 1010 M-1 range.
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Young, T. R.; Kirchner, A.; Wedd, A. G.; Xiao, Z. An Integrated Study of the Affinities of the Aβ16 Peptide for Cu(I) and Cu(II): Implications for the Catalytic Production of Reactive Oxygen Species. Metallomics 2014, 6, 505– 517, DOI: 10.1039/C4MT00001C
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An integrated study of the affinities of the Aβ16 peptide for Cu(i) and Cu(ii): implications for the catalytic production of reactive oxygen species
Young, Tessa R.; Kirchner, Angie; Wedd, Anthony G.; Xiao, Zhiguang
Metallomics (2014), 6 (3), 505-517CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
A new fluorescent probe Aβ16wwa based upon the Aβ16 peptide has been developed with two orders of magnitude greater fluorescence intensity for sensitive detection of interactions with Cu(ii). In combination with the Cu(i) probe Ferene S, it is confirmed that the Aβ16 peptide binds either Cu(i) or Cu(ii) with comparable affinities at pH 7.4 (log KID = -10.4; log KIID = -10.0). It follows from this property that the Cu-Aβ16 complex is a robust if slow catalyst for the aerial oxidn. of ascorbate with H2O2 as primary product (initial rate, ∼0.63 min-1 for Cu-Aβ16 vs. >2.5 min-1 for Cuaq2+). An integrated study of variants of this peptide identifies the major ligands and binding modes involved in its copper complexes in soln. The dependence of KID upon pH is consistent with a two-coordinate Cu(i) site in which dynamic processes exchange Cu(i) between the three available pairs of imidazole sidechains provided by His6, His13 and His14. The N-terminal amine is not involved in Cu(i) binding but is a key ligand for Cu(ii). Acetylation of the N-terminus alters the redox thermodn. gradient for the Cu center and suppresses its catalytic activity considerably. The data indicate the presence of dynamic processes that exchange Cu(ii) between the three His ligands and backbone amide at physiol. pH. His6 is identified as a key ligand for catalysis as its presence minimizes the pre-organization energy required for interchange of the two copper redox sites. These new thermodn. data strengthen structural interpretations for the Cu-Aβ complexes and provide valuable insights into the mol. mechanism by which copper chem. may induce oxidative stress in Alzheimer's disease.
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Jongbloed, W.; van Dijk, K. D.; Mulder, S. D.; van de Berg, W. D. J.; Blankenstein, M. A.; van der Flier, W.; Veerhuis, R. Clusterin Levels in Plasma Predict Cognitive Decline and Progression to Alzheimer’s Disease. J. Alzheimer’s Dis. 2015, 46, 1103– 1110, DOI: 10.3233/JAD-150036
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Clusterin Levels in Plasma Predict Cognitive Decline and Progression to Alzheimer's Disease
Jongbloed, Wesley; van Dijk, Karin D.; Mulder, Sandra D.; van de Berg, Wilma D. J.; Blankenstein, Marinus A.; van der Flier, Wiesje; Veerhuis, Robert; Nielsen, Henrietta
Journal of Alzheimer's Disease (2015), 46 (4), 1103-1110CODEN: JADIF9; ISSN:1387-2877. (IOS Press)
Background: Increased clusterin levels have been reported in brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients. Because changes are also obsd. in mild cognitive impairment (MCI), a possible relationship between clusterin levels and early neurodegenerative changes in AD was suggested. Objectives: To det. whether clusterin concns. could 1. serve as a diagnostic marker for AD, 2. predict disease progression in MCI, and 3. correlate with AD-biomarkers. Methods: Clusterin levels in CSF and plasma, as well as AD biomarker levels of Aβ 42, Tau, and pTau in CSF and Mini-Mental State Examn. scores (MMSE) were detd. in 67 controls, 50 MCI, and 107 AD patients. Repeated MMSE was obtained for 44 MCI and 72 AD patients after, on av., 2.7 years. Results: Elevated clusterin concns. in plasma, but not in CSF, were a risk factor for AD (HR 18.6; 95% CI 2.8-122), and related to cognitive decline in MCI (r=-0.38; p< 0.01). An inverse relation between plasma clusterin levels and cognitive decline was obsd. in AD patients (r=0.23; p≤0.05). In CSF, but not in plasma, clusterin levels correlated with Tau and pTau in all groups. Conclusion: Elevated plasma clusterin levels in MCI confer an increased risk for progression to AD, and more rapid cognitive decline. We speculate that clusterin levels in CSF may reflect its involvement in the earliest neurodegenerative processes assocd. with AD pathol. Whereas neither clusterin levels in CSF nor in plasma had diagnostic value, plasma clusterin levels may serve as a prognostic marker for AD.
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Banerjee, S.; Lyubchenko, Y. L. Interaction of Amyloidogenic Proteins with Membranes and Molecular Mechanism for the Development of Alzheimer’s Disease. Alzheimer’s Res. Ther. Open Access 2019, 2, 106
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Kakio, A.; Nishimoto, S.; Yanagisawa, K.; Kozutsumi, Y.; Matsuzaki, K. Interactions of Amyloid Beta-Protein with Various Gangliosides in Raft-like Membranes: Importance of GM1 Ganglioside-Bound Form as an Endogenous Seed for Alzheimer Amyloid. Biochemistry 2002, 41, 7385– 7390, DOI: 10.1021/bi0255874
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Interactions of amyloid β-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid
Kakio, Atsuko; Nishimoto, Seiichi; Yanagisawa, Katsuhiko; Kozutsumi, Yasunori; Matsuzaki, Katsumi
Biochemistry (2002), 41 (23), 7385-7390CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
GM1 ganglioside-bound amyloid β-protein (GM1-Aβ), found in brains exhibiting early pathol. changes of Alzheimer's disease (AD) plaques, has been suggested to accelerate amyloid fibril formation by acting as a seed. We have previously found using dye-labeled Aβ that Aβ recognizes a GM1 cluster, the formation of which is facilitated by cholesterol. In this study, we investigated the ganglioside species-specificity in its potency to induce a conformational change of Aβ, by which ganglioside-bound Aβ acts as a seed for Aβ fibrillogenesis, using a major ganglioside occurring in brains (GM1, GD1a, GD1b, and GT1b) in raft-like membranes composed of cholesterol and sphingomyelin. Aβ recognized ganglioside clusters, the d. of which increased with the no. of sialic acid residues. Interestingly, however, mixing of gangliosides inhibited cluster formation. In contrast, the affinities of the protein for the clusters were similar irresp. of lipid compn. and were of the order of 106 M-1 at 37°. Aβ underwent a conformational transition from an α-helix-rich structure to a β-sheet-rich structure with the increase in protein d. on the membrane. Ganglioside-bound Aβ proteins exhibited seeding abilities for amyloid formation. GM1-Aβ exhibited the strongest seeding potential, esp. under β-sheet-forming conditions. This study suggested that lipid compn. including gangliosides and cholesterol strictly controls amyloid formation.
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Sasahara, K.; Morigaki, K.; Shinya, K. Effects of Membrane Interaction and Aggregation of Amyloid β-Peptide on Lipid Mobility and Membrane Domain Structure. Phys. Chem. Chem. Phys. 2013, 15, 8929– 8939, DOI: 10.1039/c3cp44517h
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Effects of membrane interaction and aggregation of amyloid β-peptide on lipid mobility and membrane domain structure
Sasahara, Kenji; Morigaki, Kenichi; Shinya, Kyoko
Physical Chemistry Chemical Physics (2013), 15 (23), 8929-8939CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
Alzheimer's disease (AD) is the most prevalent age-dependent form of dementia, characterized by extracellular amyloid deposits comprising amyloid β-peptide (Aβ) in the cerebral cortex. Increasing evidence has indicated that ganglioside GM1 (GM1) in lipid rafts plays a pivotal role in amyloid deposition of Aβ and the related cytotoxicity in AD. Despite recent efforts to characterize Aβ-lipid interactions, the effect of Aβ aggregation on dynamic properties and organization of lipid membranes is poorly understood. In this study, we examd. the aggregation of Aβ on supported lipid bilayers contg. raft components (i.e., cholesterol, sphingomyelin, and GM1) and its effects on the membrane properties. We showed that the lateral fluidity of membranes was significantly affected by membrane binding and subsequent aggregation of Aβ. Microscopic observations of the membrane surfaces demonstrated an enhancement in phase sepn. of lipids as a result of interactions between Aβ and GM1 during induced aggregation of Aβ. The uptake of GM1 into Aβ aggregates and the attendant membrane damage were also obsd. under a microscope when the membrane-anchored aggregates were formed. On the basis of these observations, we propose that Aβ aggregates formed in the presence of lipid membranes have a latent ability to trigger the uptake of raft components accompanied by phase sepn. of lipids.
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Khondker, A.; Alsop, R. J.; Rheinstädter, M. C. Membrane-Accelerated Amyloid-β Aggregation and Formation of Cross-β Sheets. Membranes 2017, 7, 49, DOI: 10.3390/membranes7030049
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Membrane-accelerated amyloid-β aggregation and formation of cross-β sheets
Khondker, Adree; Alsop, Richard J.; Rheinstadter, Maikel C.
Membranes (Basel, Switzerland) (2017), 7 (3), 49/1-49/19CODEN: MBSEB6; ISSN:2077-0375. (MDPI AG)
Amyloid-β aggregates play a causative role in Alzheimer's disease. These aggregates are a product of the phys. environment provided by the basic neuronal membrane, composed of a lipid bilayer. The intrinsic properties of the lipid bilayer allow amyloid-β peptides to nucleate and form well-ordered cross-β sheets within the membrane. Here, we correlate the aggregation of the hydrophobic fragment of the amyloid-β protein, Aβ, with the hydrophobicity, fluidity, and charge d. of a lipid bilayer. We summarize recent biophys. studies of model membranes and relate these to the process of aggregation in physiol. systems.
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Sciacca, M. F. M.; Pappalardo, M.; Attanasio, F.; Milardi, D.; Rosa, C. L.; Grasso, D. M. Are Fibril Growth and Membrane Damage Linked Processes? An Experimental and Computational Study of IAPP12–18 and IAPP21–27 Peptides. New J. Chem. 2010, 34, 200– 207, DOI: 10.1039/B9NJ00253G
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Are fibril growth and membrane damage linked processes? An experimental and computational study of IAPP12-18 and IAPP21-27 peptides
Sciacca, Michele F. M.; Pappalardo, Matteo; Attanasio, Francesco; Milardi, Danilo; La Rosa, Carmelo; Grasso, Domenico M.
New Journal of Chemistry (2010), 34 (2), 200-207CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
Islet amyloid polypeptide (IAPP) is a 37-residue hormone known to deposit as fibrillar aggregates in pancreatic β-cells of patients affected by T2DM. Although it has been proposed that both the fibrillogenic potential and membrane-activity may play a key role in IAPP cytotoxicity, a direct causative relationship between these two properties has not yet been firmly established. More recently, it has been obsd. that membrane damage may occur independently from fiber formation of IAPP and that these properties may be encoded by different sequences of IAPP. To further check this hypothesis, the membrane-activity and aggregation properties of the two neutral segments LANFLVH (IAPP12-18) and NNFGAIL (IAPP21-27), that recent theor. studies have reported to possess the highest and the lowest fibrillogenic potential resp., have been studied by means of a combined exptl. and computational approach. The whole of the results demonstrate that if neutral peptides and lipids are employed, the most fibrillogenic peptide has the lowest membrane damaging effect and vice versa. These findings are expected to contribute to our rational understanding of the factors involved in the formation of amyloidosis and in the mechanisms of peptide-induced membrane damage.
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Sciacca, M.; Milardi, D.; Pappalardo, M.; Rosa, C. L.; Grasso, D. Role of Electrostatics in the Thermal Stability of Ubiquitin: A Combined DSC and MM Study. J. Therm. Anal. Calorim. 2006, 86, 311– 314, DOI: 10.1007/s10973-005-7467-0
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Role of electrostatics in the thermal stability of ubiquitin: a combined DSC and MM study
Sciacca, M. F. M.; Milardi, D.; Pappalardo, M.; La Rosa, C.; Grasso, D. M.
Journal of Thermal Analysis and Calorimetry (2006), 86 (2), 311-314CODEN: JTACF7; ISSN:1388-6150. (Springer)
The failure of the ubiquitin-proteasome system is involved in many diseases. Here, in order to assess the pH-induced changes in the physico-chem. properties of ubiquitin, DSC measurements have been carried out at 2.5<pH<7. Parallel 'in silico' pH titrns., suggest that there is a direct relationship between the calorimetric data and the electrostatic properties of ubiquitin. It is suggested that these pH-induced changes in the properties of ubiquitin may play a role in detg. its ability to properly conjugate with its physiol. targets.
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Grasso, D.; Grasso, G.; Guantieri, V.; Impellizzeri, G.; Rosa, C. L.; Milardi, D.; Micera, G.; Õsz, K.; Pappalardo, G.; Rizzarelli, E.; Sanna, D.; Sóvágó, I. Environmental Effects on a Prion’s Helix II Domain: Copper(II) and Membrane Interactions with PrP180–193 and Its Analogues. Chem. – Eur. J. 2006, 12, 537– 547, DOI: 10.1002/chem.200500534
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Environmental effects on a prion's helix II domain: Copper(II) and membrane interactions with PrP180-193 and its analogues
Grasso, Domenico; Grasso, Giulia; Guantieri, Valeria; Impellizzeri, Giuseppe; La Rosa, Carmelo; Milardi, Danilo; Micera, Giovanni; Osz, Katalin; Pappalardo, Giuseppe; Rizzarelli, Enrico; Sanna, Daniele; Sovago, Imre
Chemistry - A European Journal (2006), 12 (2), 537-547CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
An abnormal interaction between copper and the prion protein is believed to play a pivotal role in the pathogenesis of prion diseases. Copper binding has been mainly attributed to the N-terminal domain of the prion protein, but this hypothesis has recently been challenged in some papers which suggest that the C-terminal domain might also compete for metal anchoring. In particular, the segment corresponding to the helix II region of the prion protein, namely PrP180-193, has been shown both to bind copper and to exhibit a copper-enhanced cytotoxicity, as well as to interact with artificial membranes. The present work is aimed at extending these results by choosing the most representative model of this domain and by detg. its copper affinity. With this aim, the different role played by the electrostatic properties of the C- and N-termini of PrP180-193 (VNITIKQHTVTTTT) in detg. its conformational behavior, copper coordination and ability to perturb model membranes was investigated. Owing to the low soly. of PrP180-193, its copper affinity was evaluated by using the shorter PrPAc184-188NH2 (IKQHT) analog as a model. ESI-MS, ESR, UV/Vis, and CD measurements were carried out on the copper(II)/PrPAc184-188NH2 and copper(II)/PrP180-193NH2 systems, and showed that PrPAc184-188NH2 is a reliable model for the metal interaction with the helix II domain. The affinity of copper(II) for the helix II fragment is higher than that for the octarepeat and PrP106-126 peptides. Finally, the different ability of PrP180-193 analogs to perturb the DPPC model membrane was assessed by DSC measurements. The possible biol. consequences of these findings are also discussed briefly.
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Sciacca, M. F. M.; Pappalardo, M.; Milardi, D.; Grasso, D. M.; Rosa, C. L. Calcium-Activated Membrane Interaction of the Islet Amyloid Polypeptide: Implications in the Pathogenesis of Type II Diabetes Mellitus. Arch. Biochem. Biophys. 2008, 477, 291– 298, DOI: 10.1016/j.abb.2008.06.018
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Calcium-activated membrane interaction of the islet amyloid polypeptide: Implications in the pathogenesis of type II diabetes mellitus
Sciacca, Michele F. M.; Pappalardo, Matteo; Milardi, Danilo; Grasso, Domenico M.; La Rosa, Carmelo
Archives of Biochemistry and Biophysics (2008), 477 (2), 291-298CODEN: ABBIA4; ISSN:0003-9861. (Elsevier Inc.)
The role played by Ca2+ ions in the interaction of the human islet amyloid polypeptide (hIAPP) with model membranes has been investigated by differential scanning calorimetry (DSC) and CD expts. In particular, the interaction of hIAPP and its rat isoform (rIAPP) with zwitterionic dipalmitoyl-phosphatidylcholine (DPPC), neg. charged dipalmitoyl-phosphatidylserine (DPPS) vesicles and with a 3:1 mixts. of them, has been studied in the presence of Ca2+ ions. The expts. have evidenced that amorphous, sol. hIAPP assemblies interact with the hydrophobic core of DPPC bilayers. Conversely, the presence of Ca2+ ions is necessary to activate a preferential interaction of hIAPP with the hydrophobic core of DPPS membranes. These findings support the hypothesis that an impaired cellular homeostasis of Ca2+ ions may promote the insertion of hIAPP into the hydrophobic core of carrier vesicles which is thought to contribute to an eventual intracellular accumulation of β-sheet rich hIAPP aggregates.
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Milardi, D.; Sciacca, M. F. M.; Pappalardo, M.; Grasso, D. M.; La Rosa, C. The Role of Aromatic Side-Chains in Amyloid Growth and Membrane Interaction of the Islet Amyloid Polypeptide Fragment LANFLVH. Eur. Biophys. J. 2011, 40, 1– 12, DOI: 10.1007/s00249-010-0623-x
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The role of aromatic side-chains in amyloid growth and membrane interaction of the islet amyloid polypeptide fragment LANFLVH
Milardi, Danilo; Sciacca, Michele F. M.; Pappalardo, Matteo; Grasso, Domenico M.; Rosa, Carmelo
European Biophysics Journal (2011), 40 (1), 1-12CODEN: EBJOE8; ISSN:0175-7571. (Springer)
Human islet amyloid polypeptide (hIAPP) is known to misfold and aggregate into amyloid deposits that may be found in pancreatic tissues of patients affected by type 2 diabetes. Recent studies showed that the highly amyloidogenic peptide LANFLVH, corresponding to the N-terminal 12-18 region of IAPP, does not induce membrane damage. Here the authors assess the role played by the arom. residue Phe in driving both amyloid formation and membrane interaction of LANFLVH. To this aim, a set of variant heptapeptides in which the arom. residue Phe has been substituted with a Leu and Ala was studied. DSC and membrane-leakage expts. demonstrated that Phe substitution noticeably affects the peptide-induced changes in the thermotropic properties of the lipid bilayer but not its membrane damaging potential. Atomic force microscopy (AFM), ThT fluorescence and Congo red birefringence assays evidenced that the Phe residue is not required for fibrillogenesis, but it can influence the self-assembling kinetics. Mol. dynamics simulations have paralleled the outcome of the exptl. trials also providing informative details about the structure of the different peptide assemblies. These results support a general theory suggesting that arom. residues, although capable of affecting the self-assembly kinetics of small peptides and peptide-membrane interactions, are not essential either for amyloid formation or membrane leakage, and indicate that other factors such as β-sheet propensity, size and hydrophobicity of the side chain act synergistically to det. peptide properties.
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Di Natale, G.; Pappalardo, G.; Milardi, D.; Sciacca, M. F. M.; Attanasio, F.; La Mendola, D.; Rizzarelli, E. Membrane Interactions and Conformational Preferences of Human and Avian Prion N-Terminal Tandem Repeats: The Role of Copper(II) Ions, PH, and Membrane Mimicking Environments. J. Phys. Chem. B 2010, 114, 13830– 13838, DOI: 10.1021/jp1033036
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Membrane Interactions and Conformational Preferences of Human and Avian Prion N-Terminal Tandem Repeats: The Role of Copper(II) Ions, pH, and Membrane Mimicking Environments
Di Natale, Giuseppe; Pappalardo, Giuseppe; Milardi, Danilo; Sciacca, Michele F. M.; Attanasio, Francesco; La Mendola, Diego; Rizzarelli, Enrico
Journal of Physical Chemistry B (2010), 114 (43), 13830-13838CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
The flexible N-terminal domain of the prion protein (PrPc) is believed to play a pivotal role in both trafficking of the protein through the cell membrane and its pathogenic conversion into the β sheet-rich scrapie isoform (PrPsc). Unlike mammalian PrPc, avian prion proteins are not known to undergo any pathogenic conformational conversions. Consequently, some crit. advances in our understanding of the mol. mechanisms underlying prion pathogenesis are expected from comparative studies of the biophys. properties of the N-terminal domains of the two proteins. The present study addresses the role played by different environmental factors, i.e., copper(II), pH, and membrane-mimicking environments, in assisting the conformational preferences of huPrP60-91 and chPrP53-76, two sol. peptides encompassing the N-terminal copper(II) binding domains of the human and chicken prion proteins, resp. Moreover, the membrane interactions of huPrP60-91, chPrP53-76, and their copper(II) complexes were evaluated by Trp fluorescence in conjunction with measurements of the variation in thermotropic properties of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) unilamellar vesicles. CD expts. revealed that huPrP60-91 adopts a predominant polyproline II conformation in aq. soln. that is destabilized at basic pH or in the presence of trifluoroethanol (TFE). Unlike anionic sodium dodecyl sulfate (SDS), which seems to stabilize the polyproline II conformation further, zwitterionic dodecylphosphocholine (DPC) micelles do not affect the peptide structure. On the contrary, copper(II) promptly promotes an increase in β-turn-rich structures. Differential scanning calorimetry (DSC) and Trp fluorescence assays carried out on DPPC model membranes after incubation with huPrP60-91 showed a marked tendency of the peptide to slowly penetrate the lipid bilayer with a concomitant conformational transition toward an extended β-sheet-like structure. Such an event, which was ascribed to the hydrophobic Trp side chain residues, was shown to also depend on the level of copper(II) occupancy along the peptide. Conversely, the CD spectra of chPrP53-76 aq. solns. indicated the presence of a mixt. of random-coil/β-turn-like structures whose resulting equil. was influenced by SDS and copper(II) addn. Furthermore, chPrP53-76 did not exhibit any tendency to interact with model membranes in either the presence or absence of copper(II). The results reported here provide evidence of the different roles played by environmental factors in affecting the conformation and membrane activity of human and avian prion N-terminal domains.
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Sciacca, M. F. M.; Kotler, S. A.; Brender, J. R.; Chen, J.; Lee, D.; Ramamoorthy, A. Two-Step Mechanism of Membrane Disruption by Aβ through Membrane Fragmentation and Pore Formation. Biophys. J. 2012, 103, 702– 710, DOI: 10.1016/j.bpj.2012.06.045
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Two-Step Mechanism of Membrane Disruption by Aβ through Membrane Fragmentation and Pore Formation
Sciacca, Michele F. M.; Kotler, Samuel A.; Brender, Jeffrey R.; Chen, Jennifer; Lee, Dong-kuk; Ramamoorthy, Ayyalusamy
Biophysical Journal (2012), 103 (4), 702-710CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
Disruption of cell membranes by Aβ is believed to be one of the key components of Aβ toxicity. However, the mechanism by which this occurs is not fully understood. Here, we demonstrate that membrane disruption by Aβ occurs by a two-step process, with the initial formation of ion-selective pores followed by nonspecific fragmentation of the lipid membrane during amyloid fiber formation. Immediately after the addn. of freshly dissolved Aβ1-40, defects form on the membrane that share many of the properties of Aβ channels originally reported from single-channel elec. recording, such as cation selectivity and the ability to be blockaded by zinc. By contrast, subsequent amyloid fiber formation on the surface of the membrane fragments the membrane in a way that is not cation selective and cannot be stopped by zinc ions. Moreover, we obsd. that the presence of ganglioside enhances both the initial pore formation and the fiber-dependent membrane fragmentation process. Whereas pore formation by freshly dissolved Aβ1-40 is weakly obsd. in the absence of gangliosides, fiber-dependent membrane fragmentation can only be obsd. in their presence. These results provide insights into the toxicity of Aβ and may aid in the design of specific compds. to alleviate the neurodegeneration of Alzheimer's disease.
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Sciacca, M. F. M.; Brender, J. R.; Lee, D.-K.; Ramamoorthy, A. Phosphatidylethanolamine Enhances Amyloid Fiber-Dependent Membrane Fragmentation. Biochemistry 2012, 51, 7676– 7684, DOI: 10.1021/bi3009888
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Phosphatidylethanolamine Enhances Amyloid Fiber-Dependent Membrane Fragmentation
Sciacca, Michele F. M.; Brender, Jeffrey R.; Lee, Dong-Kuk; Ramamoorthy, Ayyalusamy
Biochemistry (2012), 51 (39), 7676-7684CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
The toxicity of amyloid-forming peptides has been hypothesized to reside in the ability of protein oligomers to interact with and disrupt the cell membrane. Much of the evidence for this hypothesis comes from in vitro expts. using model membranes. However, the accuracy of this approach depends on the ability of the model membrane to accurately mimic the cell membrane. The effect of membrane compn. has been overlooked in many studies of amyloid toxicity in model systems. By combining measurements of membrane binding, membrane permeabilization, and fiber formation, we show that lipids with the phosphatidylethanolamine (PE) headgroup strongly modulate the membrane disruption induced by IAPP (islet amyloid polypeptide protein), an amyloidogenic protein involved in type II diabetes. Our results suggest that PE lipids hamper the interaction of prefibrillar IAPP with membranes but enhance the membrane disruption correlated with the growth of fibers on the membrane surface via a detergent-like mechanism. These findings provide insights into the mechanism of membrane disruption induced by IAPP, suggesting a possible role of PE and other amyloids involved in other pathologies.
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Sciacca, M. F. M.; Milardi, D.; Messina, G. M. L.; Marletta, G.; Brender, J. R.; Ramamoorthy, A.; La Rosa, C. Cations as Switches of Amyloid-Mediated Membrane Disruption Mechanisms: Calcium and IAPP. Biophys. J. 2013, 104, 173– 184, DOI: 10.1016/j.bpj.2012.11.3811
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Cations as switches of amyloid-mediated membrane disruption mechanisms: Calcium and IAPP
Sciacca, Michele F. M.; Milardi, Danilo; Messina, Grazia M. L.; Marletta, Giovanni; Brender, Jeffrey R.; Ramamoorthy, Ayyalusamy; La Rosa, Carmelo
Biophysical Journal (2013), 104 (1), 173-184CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
Disruption of the integrity of the plasma membrane by amyloidogenic proteins is linked to the pathogenesis of a no. of common age-related diseases. Although accumulating evidence suggests that adverse environmental stressors such as unbalanced levels of metal ions may trigger amyloid-mediated membrane damage, many features of the mol. mechanisms underlying these events are unknown. Here, using human islet amyloid polypeptide (hIAPP, aka amylin), an amyloidogenic peptide assocd. with β-cell death in type 2 diabetes, the authors demonstrate that the presence of Ca2+ inhibits membrane damage occurring immediately after the interaction of freshly dissolved hIAPP with the membrane, but significantly enhances fiber-dependent membrane disruption. In particular, dye leakage, quartz crystal microbalance, at. force microscopy, and NMR expts. showed that Ca2+ promoted a shallow membrane insertion of hIAPP, which led to the removal of lipids from the bilayer through a detergent-like mechanism triggered by fiber growth. Because both types of membrane-damage mechanisms are common to amyloid toxicity by most amyloidogenic proteins, it is likely that unregulated ion homeostasis, amyloid aggregation, and membrane disruption are all parts of a self-perpetuating cycle that fuels amyloid cytotoxicity.
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Sciacca, M. F.; Monaco, I.; Rosa, C. L.; Milardi, D. The Active Role of Ca 2+ Ions in Aβ-Mediated Membrane Damage. Chem. Commun. 2018, 54, 3629– 3631, DOI: 10.1039/C8CC01132J
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The active role of Ca2+ ions in Aβ-mediated membrane damage
Sciacca, Michele F. M.; Monaco, Irene; La Rosa, Carmelo; Milardi, Danilo
Chemical Communications (Cambridge, United Kingdom) (2018), 54 (29), 3629-3631CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
Ca2+ dysregulation, membrane leakage, and amyloid-β (Aβ) growth are hallmarks of Alzheimer's disease. Here, we show that Ca2+ ions inhibit membrane damage due to amyloid channels, but enhance membrane disruption assocd. with fibers growing on the lipid surface. The similarities with IAPP suggest that this may represent a mechanism common to all proteinopathies.
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Mroczko, B.; Groblewska, M.; Litman-Zawadzka, A.; Kornhuber, J.; Lewczuk, P. Amyloid β Oligomers (AβOs) in Alzheimer’s Disease. J. Neural Transm. 2018, 125, 177– 191, DOI: 10.1007/s00702-017-1820-x
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Amyloid β oligomers (AβOs) in Alzheimer's disease
Mroczko, Barbara; Groblewska, Magdalena; Litman-Zawadzka, Ala; Kornhuber, Johannes; Lewczuk, Piotr
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Abstract
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Figure 1
Figure 1. Thioflavin T assay in the MOPS buffer. ThT traces of samples containing Aβ_1–40 20 μM alone (black curve) and in the presence of Cu²⁺ 20 μM (orange curve), Semax 20 μM (gray curve), Semax 100 μM (yellow curve), Cu²⁺ 20 μM/Semax 20 μM (blue curve), and Cu²⁺ 20 μM/Semax 100 μM (green curve). All the experiments were performed at 37 °C in the 10 mM MOPS buffer and 100 mM NaCl at pH 7.4. All traces are the average of three independent experiments.
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Figure 2
Figure 2. (A) Representative western blot of Aβ_1–42 oligomers (o Aβ) prepared in the presence of Semax (1:5) and/or copper (1:1). Aβ_1–42 incubated alone was also prepared as the control. Samples were loaded onto a 4–12% Bis–Tris SDS-PAGE gel and blotted with anti-Aβ N-terminal 1–16 mouse monoclonal antibody 6E10 (1:500). Densitometric analysis of (B) trimeric, (C) tetrameric, and (D) high molecular weight (HMW) bands quantified by the Image Studio software of the Odyssey instrument.
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Figure 3
Figure 3. Comparison of enthalpy contribution. Contribution of ΔH of each peak for LUV DMPC:DMPS in the presence of Aβ_1–40 5 μM, Aβ_1–40 5 μM + Cu²⁺ 5 μM, Aβ_1–40 5 μM + Cu²⁺ 5 μM + Semax 5 μM, and Aβ_1–40 5 μM + Cu²⁺ 5 μM + Semax 25 μM at (A) time 0 and (B) 24 h.
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Figure 4
Figure 4. Thioflavin T assay in the presence of bTLE LUVs. ThT traces of samples containing LUV bTLE 0.2 mg mL^–1 and Aβ_1–40 20 μM alone (black curve) and in the presence of Cu²⁺ 20 μM (orange curve), Semax 20 μM (gray curve), Semax 100 μM (yellow curve), Cu²⁺ 20 μM/Semax 20 μM (blue curve), and Cu²⁺ 20 μM/Semax 100 μM (green curve). All the experiments were performed at 37 °C in aCSF at pH 7.4. All traces are the average of three independent experiments.
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Figure 5
Figure 5. Dye leakage assay in the presence of bTLE LUVs. Dye release for samples containing LUV bTLE 0.2 mg mL^–1 and Aβ_1–40 20 μM alone (black curve) and in the presence of Cu²⁺ 20 μM (orange curve), Semax 20 μM (gray curve), Semax 100 μM (yellow curve), Cu²⁺ 20 μM/Semax 20 μM (blue curve), and Cu²⁺ 20 μM/Semax 100 μM (green curve). All the experiments were performed at 37 °C in aCSF at pH 7.4. All traces are the average of three independent experiments.
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Figure 6
Figure 6. Viability of d-SH-SY5Y cells after 48 h of incubation with 5 μM differently pre-incubated Aβ_1–42 oligomers with/without Semax and Cu²⁺. Results are presented as mean ± SD with n = 8 for each condition (***p ≤ 0.001with respect to untreated control; ##p ≤ 0.01 with respect to Aβ_1–42 treatment).
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  Forloni, Gianluigi; Artuso, Vladimiro; La Vitola, Pietro; Balducci, Claudia
  Movement Disorders (2016), 31 (6), 771-781CODEN: MOVDEA; ISSN:0885-3185. (Wiley-Blackwell)
  The term oligomeropathies defines the neurodegenerative disorders assocd. with protein misfolding, where small sol. aggregates (oligomers 4-200 KDa) are the cause of neuronal dysfunction and are responsible for spreading the pathol. The ability of these sol. β-sheet conformers to induce neuronal damage has been investigated in direct challenge with the monomeric and fibrillary structures, showing that only the oligomeric species affected the neurons. β amyloid oligomers were initially purified from Alzheimer brains and obtained using synthetic peptides. Together with the neuronal death, synaptic dysfunction, loss of spines, and LTP impairment were seen with the direct application of β amyloid oligomers. Similar results have been described with proteins assocd. with other neurodegenerative disorders. The biol. activities of oligomeric forms of α synuclein have been described in Parkinson's disease and Lewy body dementia. Detrimental effects have been assocd. with the oligomeric forms of prion, tau, and huntingtin, the key proteins in prion diseases, frontotemporal dementia, and Huntington's disease, resp. The mol. mechanisms of the oligomer-related toxic effects can be summarized under three headings: nonspecific perturbance of cellular and intracellular membranes, specific interaction with various cellular entities, and amyloid pore channel formation. To characterize and distinguish oligomer actions better, we compared the ability of β amyloid and α synuclein oligomers to induce cognitive impairment when applied directly into the brain in the same acute mouse model. We also investigated the role of inflammatory components. © 2016 International Parkinson and Movement Disorder Society.
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10. 10
  Deshpande, A.; Mina, E.; Glabe, C.; Busciglio, J. Different Conformations of Amyloid β Induce Neurotoxicity by Distinct Mechanisms in Human Cortical Neurons. J. Neurosci. 2006, 26, 6011– 6018, DOI: 10.1523/JNEUROSCI.1189-06.2006
  10
  Different conformations of amyloid β induce neurotoxicity by distinct mechanisms in human cortical neurons
  Deshpande, Atul; Mina, Erene; Glabe, Charles; Busciglio, Jorge
  Journal of Neuroscience (2006), 26 (22), 6011-6018CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  Characterization of sol. oligomeric amyloid β (Aβ) species in the brains of Alzheimer's disease (AD) patients and transgenic models has raised the possibility that different conformations of Aβ may contribute to AD pathol. via different mechanisms. To characterize the toxic effect of different Aβ conformations, we tested side by side the effect of well characterized Aβ oligomers (AβOs), Aβ-derived diffusible ligands (ADDLs), and fibrillar Aβ (Aβf) prepns. in human cortical neurons (HCNs). Both AβOs and ADDLs bind rapidly and with high affinity to synaptic contacts and cellular membranes. AβOs (5 μM) induced rapid and massive neuronal death. Calcium influx accelerated, but was not required for, AβO toxicity. AβOs elicited a stereotyped succession of cellular changes consistent with the activation of a mitochondrial death apoptotic pathway. At low concns. AβOs caused chronic and subtler mitochondrial alterations but minimal cell death. ADDLs induced similar toxic changes as AβOs but on a fivefold longer time scale. Higher concns. of Aβf and longer incubation times were required to produce widespread neuritic dystrophy but modest HCN cell death. Thus various Aβ species may play relevant roles in AD, causing neurotoxicity by distinct non-overlapping mechanisms affecting neuronal function and viability over multiple time courses.
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11. 11
  Giuffrida, M. L.; Caraci, F.; Pignataro, B.; Cataldo, S.; Bona, P. D.; Bruno, V.; Molinaro, G.; Pappalardo, G.; Messina, A.; Palmigiano, A.; Garozzo, D.; Nicoletti, F.; Rizzarelli, E.; Copani, A. β-Amyloid Monomers Are Neuroprotective. J. Neurosci. 2009, 29, 10582– 10587, DOI: 10.1523/JNEUROSCI.1736-09.2009
  11
  β-Amyloid monomers are neuroprotective
  Giuffrida, Maria Laura; Caraci, Filippo; Pignataro, Bruno; Cataldo, Sebastiano; De Bona, Paolo; Bruno, Valeria; Molinaro, Gemma; Pappalardo, Giuseppe; Messina, Angela; Palmigiano, Angelo; Garozzo, Domenico; Nicoletti, Ferdinando; Rizzarelli, Enrico; Copani, Agata
  Journal of Neuroscience (2009), 29 (34), 10582-10587CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  The 42-aa-long β-amyloid protein-Aβ1-42-is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). Data from AD brain, transgenic APP (amyloid precursor protein)-overexpressing mice, and neuronal cultures treated with synthetic Aβ peptides indicate that self-assocn. of Aβ1-42 monomers into sol. oligomers is required for neurotoxicity. The function of monomeric Aβ1-42 is unknown. The evidence that Aβ1-42 is present in the brain and CSF of normal individuals suggests that the peptide is physiol. active. Here we show that synthetic Aβ1-42 monomers support the survival of developing neurons under conditions of trophic deprivation and protect mature neurons against excitotoxic death, a process that contributes to the overall neurodegeneration assocd. with AD. The neuroprotective action of Aβ1-42 monomers was mediated by the activation of the PI-3-K (phosphatidylinositol-3-kinase) pathway, and involved the stimulation of IGF-1 (insulin-like growth factor-1) receptors and/or other receptors of the insulin superfamily. Interestingly, monomers of Aβ1-42 carrying the Arctic mutation (E22G) assocd. with familiar AD were not neuroprotective. We suggest that pathol. aggregation of Aβ1-42 may also cause neurodegeneration by depriving neurons of the protective activity of Aβ1-42 monomers. This "loss-of-function" hypothesis of neuronal death should be taken into consideration when designing therapies aimed at reducing Aβ burden.
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12. 12
  Wu, W.; Liu, Q.; Sun, X.; Yu, J.; Zhao, D.; Yu, Y.; Luo, J.; Hu, J.; Yu, Z.; Zhao, Y.; Li, Y. Fibrillar Seeds Alleviate Amyloid-β Cytotoxicity by Omitting Formation of Higher-Molecular-Weight Oligomers. Biochem. Biophys. Res. Commun. 2013, 439, 321– 326, DOI: 10.1016/j.bbrc.2013.08.088
  12
  Fibrillar seeds alleviate amyloid-β cytotoxicity by omitting formation of higher-molecular-weight oligomers
  Wu, Wei-hui; Liu, Qian; Sun, Xun; Yu, Ji-sheng; Zhao, De-sheng; Yu, Ye-ping; Luo, Jun-jie; Hu, Jia; Yu, Zhi-wu; Zhao, Yu-fen; Li, Yan-mei
  Biochemical and Biophysical Research Communications (2013), 439 (3), 321-326CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
  Amyloid-β (Aβ) peptides can exist in distinct forms including monomers, oligomers and fibrils, consisting of increased nos. of monomeric units. Among these, Aβ oligomers are implicated as the primary toxic species as pointed by multiple lines of evidence. It has been suggested that toxicity could be rendered by the sol. higher-mol.-wt. (high-n) Aβ oligomers. Yet, the most culpable form in the pathogenesis of Alzheimer's disease (AD) remains elusive. Moreover, the potential interaction among the insol. fibrils that have been excluded from the responsible aggregates in AD development, Aβ monomers and high-n oligomers is undetd. Here, we report that insol. Aβ fibrillar seeds can interact with Aβ monomers at the stoichiometry of 1:2 (namely, each Aβ mol. of seed can bind to two Aβ monomers at a time) facilitating the fibrillization by omitting the otherwise mandatory formation of the toxic high-n oligomers during the fibril maturation. As a result, the addn. of exogenous Aβ fibrillar seeds is seen to rescue neuronal cells from Aβ cytotoxicity presumably exerted by high-n oligomers, suggesting an unexpected protective role of Aβ fibrillar seeds.
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13. 13
  Naletova, I.; Nicoletti, V. G.; Milardi, D.; Pietropaolo, A.; Grasso, G. Copper, Differently from Zinc, Affects the Conformation, Oligomerization State and Activity of Bradykinin. Metallomics 2016, 8, 750– 761, DOI: 10.1039/C6MT00067C
  13
  Copper, differently from zinc, affects the conformation, oligomerization state and activity of bradykinin
  Naletova, Irina; Nicoletti, Vincenzo G.; Milardi, Danilo; Pietropaolo, Adriana; Grasso, Giuseppe
  Metallomics (2016), 8 (8), 750-761CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
  The sole role of bradykinin (BK) as an inflammatory mediator is controversial, as recent data also support an anti-inflammatory role for BK in Alzheimer's disease (AD). The involvement of two different receptors (B1R and B2R) could be a key to understand this issue. However, although copper and zinc dyshomeostasis has been demonstrated to be largely involved in the development of AD, a detailed study of the interaction of BK with these two metal ions has never been addressed. In this work, we have applied mass spectrometry, CD as well as computational methods in order to assess if copper and zinc have the ability to modulate the conformation and oligomerization of BK. In addn., we have correlated the chem. data with the effect of metals on the activity of BK analyzed in cell cultures by biochem. procedures. The biochem. analyses on monocyte/macrophage cell culture (THP-1 Cell Line human) in line with the effect of metals on the conformation of BK showed that the presence of copper can affect the signaling cascade mediated by the BK receptors. The results obtained show a further role of metal ions, particularly copper, in the development and outcome of neuroinflammatory diseases. The possible implications in AD are discussed.
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14. 14
  Thakur, A. K.; Srivastava, A. K.; Srinivas, V.; Chary, K. V. R.; Rao, C. M. Copper Alters Aggregation Behavior of Prion Protein and Induces Novel Interactions between Its N- and C-Terminal Regions. J. Biol. Chem. 2011, 286, 38533– 38545, DOI: 10.1074/jbc.M111.265645
  14
  Copper Alters Aggregation Behavior of Prion Protein and Induces Novel Interactions between Its N- and C-terminal Regions
  Thakur, Abhay Kumar; Srivastava, Atul Kumar; Srinivas, Volety; Chary, Kandala Venkata Ramana; Rao, Chintalagiri Mohan
  Journal of Biological Chemistry (2011), 286 (44), 38533-38545, S38533/1-S38533/9CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  Copper is reported to promote and prevent aggregation of prion protein. Conformational and functional consequences of Cu2+-binding to prion protein (PrP) are not well understood largely because most of the Cu2+-binding studies have been performed on fragments and truncated variants of the prion protein. In this context, we set out to investigate the conformational consequences of Cu2+-binding to full-length prion protein (PrP) by isothermal calorimetry, NMR, and small angle x-ray scattering. In this study, we report altered aggregation behavior of full-length PrP upon binding to Cu2+. At physiol. temp., Cu2+ did not promote aggregation suggesting that Cu2+ may not play a role in the aggregation of PrP at physiol. temp. (37 °C). However, Cu2+-bound PrP aggregated at lower temps. This temp.-dependent process is reversible. Our results show two novel intra-protein interactions upon Cu2+-binding. The N-terminal region (residues 90-120 that contain the site His-96/His-111) becomes proximal to helix-1 (residues 144-147) and its nearby loop region (residues 139-143), which may be important in preventing amyloid fibril formation in the presence of Cu2+. In addn., we obsd. another novel interaction between the N-terminal region comprising the octapeptide repeats (residues 60-91) and helix-2 (residues 174-185) of PrP. Small angle x-ray scattering studies of full-length PrP show significant compactness upon Cu2+-binding. Our results demonstrate novel long range inter-domain interactions of the N- and C-terminal regions of PrP upon Cu2+-binding, which might have physiol. significance.
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15. 15
  Attanasio, F.; Bona, P. D.; Cataldo, S.; Sciacca, M. F. M.; Milardi, D.; Pignataro, B.; Pappalardo, G. Copper(II) and Zinc(II) Dependent Effects on Aβ42 Aggregation: A CD, Th-T and SFM Study. New J. Chem. 2013, 37, 1206– 1215, DOI: 10.1039/C3NJ40999F
  15
  Copper(ii) and zinc(ii) dependent effects on Aβ42 aggregation: a CD, Th-T and SFM study
  Attanasio, Francesco; De Bona, Paolo; Cataldo, Sebastiano; Sciacca, Michele F. M.; Milardi, Danilo; Pignataro, Bruno; Pappalardo, Giuseppe
  New Journal of Chemistry (2013), 37 (4), 1206-1215CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
  Aβ aggregation is a central event in Alzheimer's disease (AD). In vitro evidence indicates that Aβ aggregation and fibrillogenesis are significantly influenced by the employed exptl. conditions. Indeed, although it is widely established that metal ions, such as copper and zinc, have significant effects on the Aβ aggregation process, their actual role in Aβ fibrillogenesis is still debated. In this work the effects of a molar excess of zinc(ii) and/or copper(ii) ions on the Aβ42 aggregation process and the morphol. of the resultant aggregates have been compared in samples exhibiting different initial conformations. CD spectroscopy, Th-T-induced fluorescence and Scanning Force Microscopy (SFM) measurements indicated that both metal ions accelerate the aggregation process, yet significantly affect the morphol. of aggregates. In particular, copper(ii) ions were the most effective in promoting non-fibrillar, amorphous Aβ aggregates. These results further support the hypothesis that an altered distribution of metal ions in neurons might drive alternative Aβ aggregation pathways.
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16. 16
  Lau, T.-L.; Ambroggio, E. E.; Tew, D. J.; Cappai, R.; Masters, C. L.; Fidelio, G. D.; Barnham, K. J.; Separovic, F. Amyloid-Beta Peptide Disruption of Lipid Membranes and the Effect of Metal Ions. J. Mol. Biol. 2006, 356, 759– 770, DOI: 10.1016/j.jmb.2005.11.091
  16
  Amyloid-β Peptide Disruption of Lipid Membranes and the Effect of Metal Ions
  Lau, Tong-Lay; Ambroggio, Ernesto E.; Tew, Deborah J.; Cappai, Roberto; Masters, Colin L.; Fidelio, Gerardo D.; Barnham, Kevin J.; Separovic, Frances
  Journal of Molecular Biology (2006), 356 (3), 759-770CODEN: JMOBAK; ISSN:0022-2836. (Elsevier B.V.)
  β-Amyloid peptide (Aβ), which is cleaved from the larger trans-membrane amyloid precursor protein, is found deposited in the brain of patients suffering from Alzheimer's disease and is linked with neurotoxicity. We report the results of studies of Aβ(1-42) and the effect of metal ions (Cu2+ and Zn2+) on model membranes using 31P and 2H solid-state NMR, fluorescence and Langmuir Blodgett monolayer methods. Both the peptide and metal ions interact with the phospholipid headgroups and the effects on the lipid bilayer and the peptide structure were different for membrane incorporated or assocd. peptides. Copper ions alone destabilize the lipid bilayer and induced formation of smaller vesicles but when Aβ(1-42) was assocd. with the bilayer membrane copper did not have this effect. CD spectroscopy indicated that Aβ(1-42) adopted more β-sheet structure when incorporated in a lipid bilayer in comparison to the assocd. peptide, which was largely unstructured. Incorporated peptides appear to disrupt the membrane more severely than assocd. peptides, which may have implications for the role of Aβ in disease states.
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17. 17
  Weibull, M. G. M.; Simonsen, S.; Oksbjerg, C. R.; Tiwari, M. K.; Hemmingsen, L. Effects of Cu(II) on the Aggregation of Amyloid-β. JBIC, J. Biol. Inorg. Chem. 2019, 24, 1197– 1215, DOI: 10.1007/s00775-019-01727-5
  17
  Effects of Cu(II) on the aggregation of amyloid-β
  Weibull, Martina G. M.; Simonsen, Signe; Oksbjerg, Cecilie R.; Tiwari, Manish K.; Hemmingsen, Lars
  JBIC, Journal of Biological Inorganic Chemistry (2019), 24 (8), 1197-1215CODEN: JJBCFA; ISSN:0949-8257. (Springer)
  A review. Aberrant aggregation of the Aβ protein is a hallmark of Alzheimer's disease (AD), but no complete characterization of the mol. level pathogenesis has been achieved. A promising hypothesis is that dysfunction of metal ion homeostasis, and consequently, the undesired interaction of metal ions with Aβ, may be central to the development of AD. Qual., most data indicate that Cu(II) induces rapid self-assembly of both Aβ40 and Aβ42 during the initial phase of the aggregation, while at longer time scales fibrillation may occur, depending on the exptl. conditions. For Aβ40 and Cu(II):Aβ ≤ 1, most data imply that low concn. of Aβ40 favors nucleation and rapid fibril elongation, while high concn. of Aβ40 favors formation of amorphous aggregates. However, there are conflicting reports on this issue. For Aβ42 and Cu(II):Aβ ≤ 1, there is consensus that the lag time is extended upon addn. of Cu(II). For Cu(II):Aβ > 1, the lag time is increased upon interaction with Cu(II), and in most cases fibrillation is not obsd., presumably because Cu(II) occupies a second more solvent-exposed binding site, which is more prone to form metal ion-bridged species and cause rapid formation of non-fibrillar aggregates. The interesting N-terminally truncated Aβ11-40 with high affinity for Cu(II), exhibits delay of fibrillation upon addn. of 0.4 equiv. Cu(II). In our view, there are still problems achieving reproducible results in this field, and we provide a shortlist of some of the pitfalls. Finally, we propose a consensus model for the effects of Cu(II) on the aggregation kinetics of Aβ.
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18. 18
  Wärmländer, S. K. T. S.; Österlund, N.; Wallin, C.; Wu, J.; Luo, J.; Tiiman, A.; Jarvet, J.; Gräslund, A. Metal Binding to the Amyloid-β Peptides in the Presence of Biomembranes: Potential Mechanisms of Cell Toxicity. JBIC, J. Biol. Inorg. Chem. 2019, 24, 1189– 1196, DOI: 10.1007/s00775-019-01723-9
  18
  Metal binding to the amyloid-β peptides in the presence of biomembranes: potential mechanisms of cell toxicity
  Warmlander Sebastian K T S; Osterlund Nicklas; Wallin Cecilia; Jarvet Juri; Graslund Astrid; Wu Jinming; Luo Jinghui; Tiiman Ann; Jarvet Juri
  Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry (2019), 24 (8), 1189-1196 ISSN:.
  The amyloid-β (Aβ) peptides are key molecules in Alzheimer's disease (AD) pathology. They interact with cellular membranes, and can bind metal ions outside the membrane. Certain oligomeric Aβ aggregates are known to induce membrane perturbations and the structure of these oligomers-and their membrane-perturbing effects-can be modulated by metal ion binding. If the bound metal ions are redox active, as e.g., Cu and Fe ions are, they will generate harmful reactive oxygen species (ROS) just outside the membrane surface. Thus, the membrane damage incurred by toxic Aβ oligomers is likely aggravated when redox-active metal ions are present. The combined interactions between Aβ oligomers, metal ions, and biomembranes may be responsible for at least some of the neuronal death in AD patients.
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19. 19
  Xu, S.; Wang, W.; Dong, X.; Sun, Y. Molecular Insight into Cu2+-Induced Conformational Transitions of Amyloid β-Protein from Fast Kinetic Analysis and Molecular Dynamics Simulations. ACS Chem. Neurosci. 2021, 12, 300– 310, DOI: 10.1021/acschemneuro.0c00502
  19
  Molecular Insight into Cu2+-Induced Conformational Transitions of Amyloid β-Protein from Fast Kinetic Analysis and Molecular Dynamics Simulations
  Xu, Shaoying; Wang, Wenjuan; Dong, Xiaoyan; Sun, Yan
  ACS Chemical Neuroscience (2021), 12 (2), 300-310CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  Cu2+-mediated amyloid β-protein (Aβ) aggregation is implicated in the pathogenesis of Alzheimer's disease, so it is of significance to understand Cu2+-mediated conformational transitions of Aβ. Herein, four Aβ mutants were created by using the environment-sensitive cyanophenylalanine to resp. substitute F4, Y10, F19, and F20 residues of Aβ40. By using stopped-flow fluorescence spectroscopy and mol. dynamics (MD) simulations, the early stage conformational transitions of the mutants mediated by Cu2+ binding were studied. The fast kinetics unveils that Cu2+ has more significant influence on the conformational changes of N-terminal (F4 and Y10) than on the central hydrophobic core (CHC, F19, and F20) under different pH conditions (pH 6.6-8.0), esp. Y10. Lag periods of the conformational transitions are obsd. for the F19 and F20 mutants at pH 8.0, indicating the slow response of the two mutation sites on the conformational transitions. More importantly, significantly longer lag periods for F20 than for F19 indicate the conduction of the transition from F19 to F20. The conduction time (difference in lag period) decreases from 4.5 s at Cu2+ = 0 to undetectable (<1 ms) at Cu2+ = 10μM. The significant difference in the response time of F19 and F20 and the fast local conformational changes of Y10 imply that the conformational transitions of Aβ start around Y10. MD simulations support the observation of hydrophobicity increase at N-terminal during the conformational transitions of Aβ-Cu2+. It also reveals that Y10 is immediately approached by Cu2+, supporting the speculation that the starting point of conformational transitions of Aβ is near Y10. The work provided mol. insight into the early stage conformational transitions of Aβ40 mediated by Cu2+.
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20. 20
  Matsuzaki, K. Formation of Toxic Amyloid Fibrils by Amyloid β-Protein on Ganglioside Clusters. Int. J. Alzheimer’s Dis. 2011, 2011, 956104, DOI: 10.4061/2011/956104
  20
  Formation of Toxic Amyloid Fibrils by Amyloid β-Protein on Ganglioside Clusters
  Matsuzaki Katsumi
  International journal of Alzheimer's disease (2011), 2011 (), 956104 ISSN:.
  It is widely accepted that the conversion of the soluble, nontoxic amyloid β-protein (Aβ) monomer to aggregated toxic Aβ rich in β-sheet structures is central to the development of Alzheimer's disease. However, the mechanism of the abnormal aggregation of Aβ in vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβ aggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβ amyloids formed in solution. Furthermore, differences between Aβ-(1-40) and Aβ-(1-42) in membrane interaction and amyloidogenesis are also emphasized.
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21. 21
  Matsuzaki, K. Physicochemical Interactions of Amyloid Beta-Peptide with Lipid Bilayers. Biochim. Biophys. Acta 2007, 1768, 1935– 1942, DOI: 10.1016/j.bbamem.2007.02.009
  21
  Physicochemical interactions of amyloid β-peptide with lipid bilayers
  Matsuzaki, Katsumi
  Biochimica et Biophysica Acta, Biomembranes (2007), 1768 (8), 1935-1942CODEN: BBBMBS; ISSN:0005-2736. (Elsevier Ltd.)
  A review. The aggregation and deposition onto neuronal cells of amyloid β-peptide (Aβ) is central to the pathogenesis of Alzheimer's disease. Accumulating evidence suggests that membranes play a catalytic role in the aggregation of Aβ. This article summarizes the structures and properties of Aβ in soln. and the physicochem. interaction of Aβ with lipid bilayers of various compns. Reasons for discrepancies between results by different research groups are discussed. The importance of ganglioside clusters in the aggregation of Aβ is emphasized. Finally, a hypothetical physicochem. cascade in the pathogenesis of the disease is proposed.
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22. 22
  Matsuzaki, K.; Kato, K.; Yanagisawa, K. Abeta Polymerization through Interaction with Membrane Gangliosides. Biochim. Biophys. Acta 2010, 1801, 868– 877, DOI: 10.1016/j.bbalip.2010.01.008
  22
  Aβ polymerization through interaction with membrane gangliosides
  Matsuzaki, Katsumi; Kato, Koichi; Yanagisawa, Katsuhiko
  Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2010), 1801 (8), 868-877CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
  A review. Clarification of the mol. and cellular mechanisms underlying the assembly of amyloid β-protein (Aβ) into insol. fibrils in the brain has been one of the biggest challenges in the research on Alzheimer disease (AD). We previously identified a novel Aβ species, which was characterized by its tight binding to GM1 ganglioside (GM1), in the brain showing early pathol. changes of AD. The ganglioside-bound Aβ (GAβ) possessed unique characteristics, including its altered immunoreactivity, which suggests its distinct conformation from native Aβ, and its strong potency to accelerate Aβ assembly into fibrils. On the basis of these characteristics, it was hypothesized that Aβ adopts an altered conformation following interaction with GM1, leading to the generation of GAβ, and then GAβ acts as an endogenous seed for Alzheimer amyloid in the brain. To date, various in vitro and in vivo studies on GAβ have revealed how Aβ binds to gangliosides, i.e., what are the favorable physicochem. and neurobiol. conditions for generating GAβ, and what is the pathol. significance of ganglioside-induced Aβ assembly in the development of AD. Interestingly, GAβ is favorably generated in the unique ganglioside-enriched (clustered), raft-like microdomains; moreover, amyloid fibrils formed in the presence of gangliosides are neurotoxic. Furthermore, the conformational change of Aβ in the presence of ganglioside has been characterized by an NMR study. In this review, we focus on the recent progress of GAβ studies and highlight the possibility that ganglioside binding is the initial and common step in the development of a part of human misfolding-type amyloidosis, including AD.
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23. 23
  Okada, T.; Ikeda, K.; Wakabayashi, M.; Ogawa, M.; Matsuzaki, K. Formation of Toxic Abeta(1-40) Fibrils on GM1 Ganglioside-Containing Membranes Mimicking Lipid Rafts: Polymorphisms in Abeta(1-40) Fibrils. J. Mol. Biol. 2008, 382, 1066– 1074, DOI: 10.1016/j.jmb.2008.07.072
  23
  Formation of Toxic Aβ(1-40) Fibrils on GM1 Ganglioside-Containing Membranes Mimicking Lipid Rafts: Polymorphisms in Aβ(1-40) Fibrils
  Okada, Takuma; Ikeda, Keisuke; Wakabayashi, Masaki; Ogawa, Mariko; Matsuzaki, Katsumi
  Journal of Molecular Biology (2008), 382 (4), 1066-1074CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)
  The abnormal aggregation and deposition of amyloid β protein (Aβ) on neuronal cells are crit. to the onset of Alzheimer's disease. The entity (oligomers or fibrils) of toxic Aβ species responsible for the pathogenesis of the disease has been controversial. The authors have reported that the Aβ aggregates on ganglioside-rich domains of neuronal PC12 cells as well as in raft-like model membranes. Here, we identified toxic Aβ(1-40) aggregates formed with GM1-ganglioside-contg. membranes. Aβ(1-40) was incubated with raft-like liposomes composed of GM1/cholesterol/sphingomyelin at 1:2:2 and 37 °C. After a lag period, toxic amyloid fibrils with a width of 12 nm were formed and subsequently laterally assembled with slight changes in their secondary structure as confirmed by viability assay, thioflavin-T fluorescence, CD, and transmission electron microscopy. In striking contrast, Aβ fibrils formed without membranes were thinner (6.7 nm) and much less toxic because of weaker binding to cell membranes and a smaller surface hydrophobicity. This study suggests that toxic Aβ(1-40) species formed on membranes are not sol. oligomers but amyloid fibrils and that Aβ(1-40) fibrils exhibit polymorphisms.
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24. 24
  Ogawa, M.; Tsukuda, M.; Yamaguchi, T.; Ikeda, K.; Okada, T.; Yano, Y.; Hoshino, M.; Matsuzaki, K. Ganglioside-Mediated Aggregation of Amyloid β-Proteins (Aβ): Comparison between Aβ-(1-42) and Aβ-(1-40). J. Neurochem. 2011, 116, 851– 857, DOI: 10.1111/j.1471-4159.2010.06997.x
  24
  Ganglioside-mediated aggregation of amyloid β-proteins (Aβ): comparison between Aβ-(1-42) and Aβ-(1-40)
  Ogawa, Mariko; Tsukuda, Miho; Yamaguchi, Takahiro; Ikeda, Keisuke; Okada, Takuma; Yano, Yoshiaki; Hoshino, Masaru; Matsuzaki, Katsumi
  Journal of Neurochemistry (2011), 116 (5), 851-857CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
  Conversion of the sol., non-toxic amyloid β-protein (Aβ) into an aggregated, toxic form rich in β-sheets is considered a key step in the development of Alzheimer's disease. Accumulating evidence suggests that lipid rafts in membranes play a pivotal role in this process. We have proposed that Aβ-(1-40) specifically bound to a ganglioside cluster forms cytotoxic fibrils via a conformational transition from an α-helix-rich structure to a β-sheet-rich one. In the present study, we compared the interaction of Aβ-(1-40) and Aβ-(1-42) with both model and living cell membranes. Aβ-(1-42) exhibited lipid specificity and affinity similar to Aβ-(1-40), though its amyloidogenic activity was more than 10-fold that of Aβ-(1-40). Antibody staining expts., using the A11 antibody specific to Aβ oligomers, demonstrated that oligomers were not detected during the aggregation process, and cell death was obsd. only after significant accumulation of the proteins, suggesting that the fibril-induced disruption of cell membranes leads to the cytotoxicity. Furthermore, we succeeded in visualizing fibrils formed on cell membranes using total internal reflection fluorescence microscopy. Aβ-(1-40) formed long fibrils appeared to be laterally co-assembled and short.
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25. 25
  Chen, W.-T.; Liao, Y.-H.; Yu, H.-M.; Cheng, I. H.; Chen, Y.-R. Distinct Effects of Zn²⁺, Cu²⁺, Fe³⁺, and Al³⁺ on Amyloid-β Stability, Oligomerization, and Aggregation: AMYLOID-β DESTABILIZATION PROMOTES ANNULAR PROTOFIBRIL FORMATION *. J. Biol. Chem. 2011, 286, 9646– 9656, DOI: 10.1074/jbc.M110.177246
  25
  Distinct Effects of Zn2+, Cu2+, Fe3+, and Al3+ on Amyloid-β Stability, Oligomerization, and Aggregation: Amyloid-β destabilization promotes annular protofibril formation
  Chen, Wei-Ting; Liao, Yi-Hung; Yu, Hui-Ming; Cheng, Irene H.; Chen, Yun-Ru
  Journal of Biological Chemistry (2011), 286 (11), 9646-9656CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  Abnormally high concns. of Zn2+, Cu2+, and Fe3+ are present along with amyloid-β (Aβ) in the senile plaques in Alzheimer disease, where Al3+ is also detected. Aβ aggregation is the key pathogenic event in Alzheimer disease, where Aβ oligomers are the major culprits. The fundamental mechanism of these metal ions on Aβ remains elusive. Here, we employ 4,4'-Bis(1-anilinonaphthalene 8-sulfonate) and tyrosine fluorescence, CD, stopped flow fluorescence, guanidine hydrochloride denaturation, and photo-induced crosslinking to elucidate the effect of Zn2+, Cu2+, Fe3+, and Al3+ on Aβ at the early stage of the aggregation. Furthermore, thioflavin T assay, dot blotting, and TEM are utilized to examine Aβ aggregation. Our results show that Al3+ and Zn2+, but not Cu2+ and Fe3+, induce larger hydrophobic exposures of Aβ conformation, resulting in its significant destabilization at the early stage. The metal ion binding induces Aβ conformational changes with micromolar binding affinities and millisecond binding kinetics. Cu2+ and Zn2+ induce similar assembly of transiently appearing Aβ oligomers at the early state. During the aggregation, we found that Zn2+ exclusively promotes the annular protofibril formation without undergoing a nucleation process, whereas Cu2+ and Fe3+ inhibit fibril formation by prolonging the nucleation phases. Al3+ also inhibits fibril formation; however, the annular oligomers co-exist in the aggregation pathway. In conclusion, Zn2+, Cu2+, Fe3+, and Al3+ adopt distinct folding and aggregation mechanisms to affect Aβ, where Aβ destabilization promotes annular protofibril formation. Our study facilitates the understanding of annular Aβ oligomer formation upon metal ion binding.
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26. 26
  Frederickson, C. J.; Koh, J.-Y.; Bush, A. I. The Neurobiology of Zinc in Health and Disease. Nat. Rev. Neurosci. 2005, 6, 449– 462, DOI: 10.1038/nrn1671
  26
  The neurobiology of zinc in health and disease
  Frederickson, Christopher J.; Koh, Jae-Young; Bush, Ashley I.
  Nature Reviews Neuroscience (2005), 6 (6), 449-462CODEN: NRNAAN; ISSN:1471-003X. (Nature Publishing Group)
  A review. The use of zinc in medicinal skin creams was mentioned in Egyptian papyri from 2000 BC (for example, the Smith Papyrus), and zinc has apparently been used fairly steadily throughout Roman and modern times (for example, as the American lotion Calamine named for its zinc ore). It is somewhat ironic that zinc is a relatively late addn. to the pantheon of signal ions in biol. and medicine. The no. of Zn biol. functions, health implications, and emerging pharmacol. targets indicate that Zn might be 'the calcium of the 21st century'.
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27. 27
  Lovell, M. A.; Robertson, J. D.; Teesdale, W. J.; Campbell, J. L.; Markesbery, W. R. Copper, Iron and Zinc in Alzheimer’s Disease Senile Plaques. J. Neurol. Sci. 1998, 158, 47– 52, DOI: 10.1016/s0022-510x(98)00092-6
  27
  Copper, iron and zinc in Alzheimer's disease senile plaques
  Lovell, M. A.; Robertson, J. D.; Teesdale, W. J.; Campbell, J. L.; Markesbery, W. R.
  Journal of the Neurological Sciences (1998), 158 (1), 47-52CODEN: JNSCAG; ISSN:0022-510X. (Elsevier Science B.V.)
  Concns. of copper (Cu), iron (Fe) and zinc (Zn) were measured in the rims and cores of senile plaques (SP) and in the neuropil of the amygdala of nine Alzheimer's disease (AD) patients and in the neuropil of the amygdala of five neurol. normal control subjects using micro particle-induced X-ray emission (micro-PIXE). Comparison of SP rim and core values revealed no significant differences between levels of Cu, Fe or Zn. Zinc and Fe in SP rims and cores were significantly elevated in AD compared with AD neuropil (P<0.05). Copper was significantly elevated (P<0.05) in the rim of SP compared with AD neuropil. Comparison of AD and control neuropil revealed a significant (P<0.05) elevation of Zn in AD subjects. The elevation of these elements in SP in AD is of interest in light of the observation that Cu, Fe and particularly Zn, can accelerate aggregation of amyloid beta peptide.
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28. 28
  Somavarapu, A. K.; Shen, F.; Teilum, K.; Zhang, J.; Mossin, S.; Thulstrup, P. W.; Bjerrum, M. J.; Tiwari, M. K.; Szunyogh, D.; Søtofte, P. M.; Kepp, K. P.; Hemmingsen, L. The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+ −Aβ Complex. Chemistry 2017, 23, 13591– 13595, DOI: 10.1002/chem.201703440
  28
  The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+-Aβ Complex
  Somavarapu, Arun K.; Shen, Fei; Teilum, Kaare; Zhang, Jingdong; Mossin, Susanne; Thulstrup, Peter W.; Bjerrum, Morten J.; Tiwari, Manish K.; Szunyogh, Daniel; Sotofte, Peter M.; Kepp, Kasper P.; Hemmingsen, Lars
  Chemistry - A European Journal (2017), 23 (55), 13591-13595CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A prominent current hypothesis is that impaired metal ion homeostasis may contribute to Alzheimer's disease (AD). We elucidate the interaction of Cu2+ with wild-type (WT) Aβ1-40 and the genetic variants A2T and A2V which display increasing pathogenicity as A2T<WT<A2V. Cu2+ significantly extends the lag phase in aggregation kinetics, in particular for the pathogenic A2V variant. Addnl., a rapid, initial, low intensity ThT response is obsd., possibly reflecting formation of Cu2+ induced amorphous aggregates, as supported by at. force microscopy (AFM) and CD spectroscopy, again most notably for the A2V variant. ESR (EPR) spectroscopy gives pKa values for transition between two Cu2+ coordination geometries (component I and II) of 7.4 (A2T), 7.9 (WT), and 8.4 (A2V), i.e., component I is stabilized at physiol. pH in the order A2T < WT < A2V. 1H NMR relaxation exhibits the same trend for the non-coordinating arom. residues (A2T<WT<A2V), and implies markedly faster inter-peptide Cu2+ exchange for the A2V variant than for WT and A2T. We therefore hypothesize that component I of the Cu-Aβ complex is related to pathogenicity, accounting for both the pathogenic nature of the A2V variant and the protective nature of the A2T variant.
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29. 29
  Raman, B.; Ban, T.; Yamaguchi, K.-I.; Sakai, M.; Kawai, T.; Naiki, H.; Goto, Y. Metal Ion-Dependent Effects of Clioquinol on the Fibril Growth of an Amyloid β Peptide. J. Biol. Chem. 2005, 280, 16157– 16162, DOI: 10.1074/jbc.M500309200
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  Metal ion-dependent effects of clioquinol on the fibril growth of an amyloid β peptide
  Raman, Bakthisaran; Ban, Tadato; Yamaguchi, Kei-ichi; Sakai, Miyo; Kawai, Tomoji; Naiki, Hironobu; Goto, Yuji
  Journal of Biological Chemistry (2005), 280 (16), 16157-16162CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  Although metal ions such as Cu2+, Zn2+, and Fe3+ are implicated to play a key role in Alzheimer's disease, their role is rather complex, and comprehensive understanding is not yet obtained. We show that Cu2+ and Zn2+ but not Fe3+ renders the amyloid β peptide, Aβ1-40, nonfibrillogenic in nature. However, preformed fibrils of Aβ1-40 were stable when treated with these metal ions. Consequently, fibril growth of Aβ1-40 could be switched on/off by switching the mol. between its apo- and holo-forms. Clioquinol, a potential drug for Alzheimer disease, induced resumption of the Cu2+-suppressed but not the Zn2+-suppressed fibril growth of Aβ1-40. The obsd. synergistic effect of clioquinol and Zn2+ suggests that Zn2+-clioquinol complex effectively retards fibril growth. Thus, clioquinol has dual effects; although it disaggregates the metal ion-induced aggregates of Aβ1-40 through metal chelation, it further retards the fibril growth along with Zn2+. These results indicate the mechanism of metal ions in suppressing Aβ amyloid formation, as well as providing information toward the use of metal ion chelators, particularly clioquinol, as potential drugs for Alzheimer's disease.
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30. 30
  Zhang, Y.; Rempel, D. L.; Zhang, J.; Sharma, A. K.; Mirica, L. M.; Gross, M. L. Pulsed Hydrogen–Deuterium Exchange Mass Spectrometry Probes Conformational Changes in Amyloid Beta (Aβ) Peptide Aggregation. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 14604– 14609, DOI: 10.1073/pnas.1309175110
  30
  Pulsed hydrogen-deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aβ) peptide aggregation
  Zhang, Ying; Rempel, Don L.; Zhang, Jun; Sharma, Anuj K.; Mirica, Liviu M.; Gross, Michael L.
  Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (36), 14604-14609,S14604/1-S14604/6CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Probing the conformational changes of amyloid beta (Aβ) peptide aggregation is challenging, owing to the vast heterogeneity of the resulting sol. aggregates. To investigate the formation of these aggregates in soln., we designed a mass spectrometry (MS)-based biophys. approach and applied it to the formation of sol. aggregates of the Aβ42 peptide, the proposed causative agent in Alzheimer's disease. The approach incorporates pulsed hydrogen-deuterium exchange (HDX) coupled with MS anal. The combined approach provides evidence for a self-catalyzed aggregation with a lag phase, as obsd. previously by fluorescence methods. Unlike those approaches, pulsed hydrogen-deuterium exchange does not require modified Aβ42 (e.g., labeling with a fluorophore). Furthermore, the approach reveals that the center region of Aβ42 is first to aggregate, followed by the C and N termini. We also found that the lag phase in the aggregation of sol. species is affected by temp. and Cu2+ ions. This MS approach has sufficient structural resoln. to allow interrogation of Aβ aggregation in physiol. relevant environments. This platform should be generally useful for investigating the aggregation of other amyloid-forming proteins and neurotoxic sol. peptide aggregates.
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31. 31
  Dai, X.-L.; Sun, Y.-X.; Jiang, Z.-F. Cu(II) Potentiation of Alzheimer Abeta1-40 Cytotoxicity and Transition on Its Secondary Structure. Acta Biochim. Biophys. Sin. 2006, 38, 765– 772, DOI: 10.1111/j.1745-7270.2006.00228.x
  31
  Cu(II) potentiation of Alzheimer Aβ1-40 cytotoxicity and transition on its secondary structure
  Dai, Xue-Ling; Sun, Ya-Xuan; Jiang, Zhao-Feng
  Acta Biochimica et Biophysica Sinica (2006), 38 (11), 765-772CODEN: ABBSC2; ISSN:1672-9145. (Blackwell Publishing Asia Pty Ltd.)
  Mounting evidence has shown that dyshomeostasis of the redox-active biometals such as Cu and Fe can lead to oxidative stress, which plays a key role in the neuropathol. of Alzheimer's disease (AD). Here we demonstrate that with the formation of Cu(II)·Aβ1-40 complexes, copper markedly potentiates the neurotoxicity exhibited by β-amyloid peptide (Aβ). A greater amt. of hydrogen peroxide was released when Cu(II)·Aβ1-40 complexes was added to the xanthine oxidase/xanthine system detected by potassium iodide spectrophotometry. Copper bound to Aβ1-40 was obsd. by ESR (EPR) spectroscopy. CD studies indicated that copper chelation could cause a structural transition of Aβ. The addn. of copper to Aβ introduced an increase on β-sheet as well as α-helix, which may be responsible for the aggregation of Aβ. We hypothesized that Aβ aggregation induced by copper may be responsible for local injury in AD. The interaction between Cu2+ and Aβ also provides a possible mechanism for the enrichment of metal ions in amyloid plaques in the AD brain.
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32. 32
  Ha, C.; Ryu, J.; Park, C. B. Metal Ions Differentially Influence the Aggregation and Deposition of Alzheimer’s Beta-Amyloid on a Solid Template. Biochemistry 2007, 46, 6118– 6125, DOI: 10.1021/bi7000032
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  Metal Ions Differentially Influence the Aggregation and Deposition of Alzheimer's β-Amyloid on a Solid Template
  Ha, Chanki; Ryu, Jungki; Park, Chan Beum
  Biochemistry (2007), 46 (20), 6118-6125CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  The abnormal deposition and aggregation of β-amyloid (Aβ) on brain tissues are considered to be one of the characteristic neuropathol. features of Alzheimer's disease (AD). Environmental conditions such as metal ions, pH, and cell membranes are assocd. with Aβ deposition and plaque formation. According to the amyloid cascade hypothesis of AD, the deposition of Aβ42 oligomers as diffuse plaques in vivo is an important earliest event, leading to the formation of fibrillar amyloid plaques by the further accumulation of sol. Aβ under certain environmental conditions. In order to characterize the effect of metal ions on amyloid deposition and plaque growth on a solid surface, we prepd. a synthetic template by immobilizing Aβ oligomers onto a N-hydroxysuccinimide ester-activated solid surface. According to our study using ex situ at. force microscopy (AFM), Fourier transform IR spectroscopy (FT-IR), and thioflavin T (ThT) fluorescence spectroscopy, Cu2+ and Zn2+ ions accelerated both Aβ40 and Aβ42 deposition but resulted only in the formation of "amorphous" aggregates. In contrast, Fe3+ induced the deposition of "fibrillar" amyloid plaques at neutral pH. Under mildly acidic environments, the formation of fibrillar amyloid plaques was not induced by any metal ion tested in this work. Using secondary ion mass spectroscopy (SIMS) anal., we found that binding Cu ions to Aβ deposits on a solid template occurred by the possible redn. of Cu ions during the interaction of Aβ with Cu2+. Our results may provide insights into the role of metal ions on the formation of fibrillar or amorphous amyloid plaques in AD.
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33. 33
  Greco, V.; Naletova, I.; Ahmed, I. M. M.; Vaccaro, S.; Messina, L.; La Mendola, D.; Bellia, F.; Sciuto, S.; Satriano, C.; Rizzarelli, E. Hyaluronan-Carnosine Conjugates Inhibit Aβ Aggregation and Toxicity. Sci. Rep. 2020, 10, 15998, DOI: 10.1038/s41598-020-72989-2
  33
  Hyaluronan-carnosine conjugates inhibit Aβ aggregation and toxicity
  Greco, Valentina; Naletova, Irina; Ahmed, Ikhlas M. M.; Vaccaro, Susanna; Messina, Luciano; La Mendola, Diego; Bellia, Francesco; Sciuto, Sebastiano; Satriano, Cristina; Rizzarelli, Enrico
  Scientific Reports (2020), 10 (1), 15998CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
  Alzheimer's disease is the most common neurodegenerative disorder. Finding a pharmacol. approach that cures and/or prevents the onset of this devastating disease represents an important challenge for researchers. According to the amyloid cascade hypothesis, increases in extracellular amyloid-β (Aβ) levels give rise to different aggregated species, such as protofibrils, fibrils and oligomers, with oligomers being the more toxic species for cells. Many efforts have recently been focused on multi-target ligands to address the multiple events that occur concurrently with toxic aggregation at the onset of the disease. Moreover, investigating the effect of endogenous compds. or a combination thereof is a promising approach to prevent the side effects of entirely synthetic drugs. In this work, we report the synthesis, structural characterization and Aβ antiaggregant ability of new derivs. of hyaluronic acid (Hy, 200 and 700 kDa) functionalized with carnosine (Car), a multi-functional natural dipeptide. The bioactive substances (HyCar) inhibit the formation of amyloid-type aggregates of Aβ42 more than the parent compds.; this effect is proportional to Car loading. Furthermore, the HyCar derivs. are able to dissolve the amyloid fibrils and to reduce Aβ-induced toxicity in vitro. The enzymic degrdn. of Aβ is also affected by the interaction with HyCar.
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34. 34
  Attanasio, F.; Convertino, M.; Magno, A.; Caflisch, A.; Corazza, A.; Haridas, H.; Esposito, G.; Cataldo, S.; Pignataro, B.; Milardi, D.; Rizzarelli, E. Carnosine Inhibits Aβ42 Aggregation by Perturbing the H-Bond Network in and around the Central Hydrophobic Cluster. ChemBioChem 2013, 14, 583– 592, DOI: 10.1002/cbic.201200704
  34
  Carnosine Inhibits Aβ42 Aggregation by Perturbing the H-Bond Network in and around the Central Hydrophobic Cluster
  Attanasio, Francesco; Convertino, Marino; Magno, Andrea; Caflisch, Amedeo; Corazza, Alessandra; Haridas, Haritha; Esposito, Gennaro; Cataldo, Sebastiano; Pignataro, Bruno; Milardi, Danilo; Rizzarelli, Enrico
  ChemBioChem (2013), 14 (5), 583-592CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Aggregation of the amyloid-β peptide (Aβ) into fibrillar structures is a hallmark of Alzheimer's disease. Thus, preventing self-assembly of the Aβ peptide is an attractive therapeutic strategy. Here, we used exptl. techniques and atomistic simulations to investigate the influence of carnosine, a dipeptide naturally occurring in the brain, on Aβ aggregation. Scanning force microscopy, CD and thioflavin T fluorescence expts. showed that carnosine does not modify the conformational features of Aβ42 but nonetheless inhibits amyloid growth. Mol. dynamics (MD) simulations indicated that carnosine interacts transiently with monomeric Aβ42 by salt bridges with charged side chains, and van der Waals contacts with residues in and around the central hydrophobic cluster (17LVFFA21). NMR expts. on the non-aggregative fragment Aβ12-28 did not evidence specific intermol. interactions between the peptide and carnosine, in agreement with MD simulations. However, a close inspection of the spectra revealed that carnosine interferes with the local propensity of the peptide to form backbone hydrogen bonds close to the central hydrophobic cluster (residues E22, S26 and N27). Finally, MD simulations of aggregation-prone Aβ heptapeptide segments show that carnosine reduces the propensity to form intermol. backbone hydrogen bonds in the region 18-24. Taken together, the exptl. and simulation results (cumulative MD sampling of 0.2 ms) suggest that, despite the inability of carnosine to form stable contacts with Aβ, it might block the pathway toward toxic aggregates by perturbing the hydrogen bond network near residues with key roles in fibrillogenesis.
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35. 35
  Wang, Q.; Liang, G.; Zhang, M.; Zhao, J.; Patel, K.; Yu, X.; Zhao, C.; Ding, B.; Zhang, G.; Zhou, F.; De Zheng, J. Novo Design of Self-Assembled Hexapeptides as β-Amyloid (Aβ) Peptide Inhibitors. ACS Chem. Neurosci. 2014, 5, 972– 981, DOI: 10.1021/cn500165s
  35
  De Novo Design of Self-Assembled Hexapeptides as β-Amyloid (Aβ) Peptide Inhibitors
  Wang, Qiuming; Liang, Guizhao; Zhang, Mingzhen; Zhao, Jun; Patel, Kunal; Yu, Xiang; Zhao, Chao; Ding, Binrong; Zhang, Ge; Zhou, Feimeng; Zheng, Jie
  ACS Chemical Neuroscience (2014), 5 (10), 972-981CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  The ability of peptides to construct specific secondary structures provides a useful function for biomaterial design that cannot be achieved with traditional org. mols. and polymers. Inhibition of amyloid formation is a promising therapeutic approach for the treatment of neurodegenerative diseases. Existing peptide-based inhibitors are mainly derived from original amyloid sequences, which have very limited sequence diversity and activity. It is highly desirable to explore other peptide-based inhibitors that are not directly derived from amyloid sequences. Here, we develop a hybrid high-throughput computational method to efficiently screen and design hexapeptide inhibitors against amyloid-β (Aβ) aggregation and toxicity from the first principle. Computationally screened/designed inhibitors are then validated for their inhibition activity using biophys. expts. We propose and demonstrate a proof-of-concept of the "like-interacts-like" design principle that the self-assembling peptides are able to interact strongly with conformationally similar motifs of Aβ peptides and to competitively reduce Aβ-Aβ interactions, thus preventing Aβ aggregation and Aβ-induced toxicity. Such a de novo design can also be generally applicable to design new peptide inhibitors against other amyloid diseases, beyond traditional peptide inhibitors with homologous sequences to parent amyloid peptides.
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36. 36
  Barrera Guisasola, E. E.; Andujar, S. A.; Hubin, E.; Broersen, K.; Kraan, I. M.; Méndez, L.; Delpiccolo, C. M. L.; Masman, M. F.; Rodríguez, A. M.; Enriz, R. D. New Mimetic Peptides Inhibitors of Αβ Aggregation. Molecular Guidance for Rational Drug Design. Eur. J. Med. Chem. 2015, 95, 136– 152, DOI: 10.1016/j.ejmech.2015.03.042
  36
  New mimetic peptides inhibitors of Αβ aggregation. Molecular guidance for rational drug design
  Barrera Guisasola, Exequiel E.; Andujar, Sebastian A.; Hubin, Ellen; Broersen, Kerensa; Kraan, Ivonne M.; Mendez, Luciana; Delpiccolo, Carina M. L.; Masman, Marcelo F.; Rodriguez, Ana M.; Enriz, Ricardo D.
  European Journal of Medicinal Chemistry (2015), 95 (), 136-152CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
  A new series of mimetic peptides possessing a significant Aβ aggregation modulating effect was reported here. These compds. were obtained based on a mol. modeling study which allowed us to perform a structural-based virtual selection. Monitoring Aβ aggregation by thioflavin T fluorescence and TEM revealed that fibril formation was significantly decreased upon prolonged incubation in presence of the active compds. Dot blot anal. suggested a decrease of sol. oligomers strongly assocd. with cognitive decline in Alzheimer's disease. For the mol. dynamics simulations, the authors used an Aβ42 pentameric model where the compds. were docked using a blind docking technique. To analyze the dynamic behavior of the complexes, extensive mol. dynamics simulations were carried out in explicit water. The authors also measured parameters or descriptors that allowed us to quantify the effect of these compds. as potential inhibitors of Aβ aggregation. Thus, significant alterations in the structure of the Aβ42 protofibril model were identified. Among others the authors obsd. the destruction of the regular helical twist, the loss of a stabilizing salt bridge and the loss of a stabilizing hydrophobic interaction in the β1 region. The results may be helpful in the structural identification and understanding of the min. structural requirements for these mols. and might provide a guide in the design of new aggregation modulating ligands.
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37. 37
  Ryan, P.; Patel, B.; Makwana, V.; Jadhav, H. R.; Kiefel, M.; Davey, A.; Reekie, T. A.; Rudrawar, S.; Kassiou, M. Peptides, Peptidomimetics, and Carbohydrate-Peptide Conjugates as Amyloidogenic Aggregation Inhibitors for Alzheimer’s Disease. ACS Chem. Neurosci. 2018, 9, 1530– 1551, DOI: 10.1021/acschemneuro.8b00185
  37
  Peptides, Peptidomimetics, and Carbohydrate-Peptide Conjugates as Amyloidogenic Aggregation Inhibitors for Alzheimer's Disease
  Ryan, Philip; Patel, Bhautikkumar; Makwana, Vivek; Jadhav, Hemant R.; Kiefel, Milton; Davey, Andrew; Reekie, Tristan A.; Rudrawar, Santosh; Kassiou, Michael
  ACS Chemical Neuroscience (2018), 9 (7), 1530-1551CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  Alzheimer's disease (AD) is a progressive neurodegenerative disorder accounting for 60-80% of dementia cases. For many years, AD causality was attributed to amyloid-β (Aβ) aggregated species. Recently, multiple therapies that target Aβ aggregation have failed in clin. trials, since Aβ aggregation is found in AD and healthy patients. Attention has therefore shifted towards the aggregation of the peptide tau as a major driver of AD. Numerous inhibitors of tau-based pathol. have recently been developed. Diagnosis of AD has shifted from measuring late stage senile plaques to early-stage biomarkers, amyloid and tau monomers and oligomeric assemblies. Synthetic peptides and some deriv. structures are being explored for use as theranostic tools as they possess the capacity to both bind the biomarkers, and to inhibit their pathol. self-assembly. Several studies have demonstrated that O-linked glycan addn. can significantly alter amyloid aggregation kinetics. Furthermore, natural O-glycosylation of amyloid-forming proteins, including amyloid precursor protein (APP), tau and α-synuclein, promote alternative non-amyloidogenic processing pathways. As such, glycopeptides and related peptidomimetics are being investigated within the AD field. Here we review advancements made in the last five years, as well as the arrival of sugar-based derivs.
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38. 38
  Asadbegi, M.; Shamloo, A. Identification of a Novel Multifunctional Ligand for Simultaneous Inhibition of Amyloid-Beta (Aβ42) and Chelation of Zinc Metal Ion. ACS Chem. Neurosci. 2019, 10, 4619– 4632, DOI: 10.1021/acschemneuro.9b00468
  38
  Identification of a Novel Multifunctional Ligand for Simultaneous Inhibition of Amyloid-Beta (Aβ42) and Chelation of Zinc Metal Ion
  Asadbegi, Mohsen; Shamloo, Amir
  ACS Chemical Neuroscience (2019), 10 (11), 4619-4632CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  Zinc binding to β-amyloid structure could promote amyloid-β aggregation, as well as reactive oxygen species (ROS) prodn., as suggested in many exptl. and theor. studies. Therefore, the introduction of multifunctional drugs, capable of chelating zinc metal ion and inhibiting Aβ aggregation, is a promising strategy in the development of AD treatment. The present study has evaluated the efficacy of a new bifunctional peptide drug using mol. docking and mol. dynamics (MD) simulations. This drug composes of two different domains: inhibitor domain, obtained from C-terminal hydrophobic region of Aβ and Zn2+ chelating domain, derived from rapeseed meal, merging with a linker. The multifunctionality of the ligand was evaluated using a comprehensive set of MD simulations spanning up to 3.2 μs including Aβ relaxation, ligand-Zn2+ bilateral interaction, and more importantly, ligand-Zn2+-Aβ42 trilateral interactions. Anal. of the results strongly indicated that the bifunctional ligand can chelate zinc metal ion and avoid Aβ aggregation simultaneously. The present study illustrated that the proposed ligand has considerable hydrophobic interactions and hydrogen bonding with the monomeric Aβ in the presence of zinc metal ion. Therefore, in light of these considerable interactions and contacts, the α-helical structure of Aβ have been enhanced, while preventing the β-sheet formation as well as protecting the α-helix native structure. Furthermore, the anal. of interactions between Aβ and ligand-zinc complex revealed that the zinc metal ion is coordinated to Met13, the ending residue of the ligand and merely one residue in Aβ. The results have approved the previous exptl. and theor. findings in the literature about Aβ interactions with zinc metal ion and also Aβ interactions with the first domain of the proposed ligand. Moreover, the current research has evaluated the chelation using MD simulation and linear interaction energy (LIE) method and the result has been satisfactorily verified with previous exptl. and theor. (DFT) studies.
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39. 39
  Stellato, F.; Fusco, Z.; Chiaraluce, R.; Consalvi, V.; Dinarelli, S.; Placidi, E.; Petrosino, M.; Rossi, G. C.; Minicozzi, V.; Morante, S. The Effect of β-Sheet Breaker Peptides on Metal Associated Amyloid-β Peptide Aggregation Process. Biophys. Chem. 2017, 229, 110– 114, DOI: 10.1016/j.bpc.2017.05.005
  39
  The effect of β-sheet breaker peptides on metal associated Amyloid-β peptide aggregation process
  Stellato, F.; Fusco, Z.; Chiaraluce, R.; Consalvi, V.; Dinarelli, S.; Placidi, E.; Petrosino, M.; Rossi, G. C.; Minicozzi, V.; Morante, S.
  Biophysical Chemistry (2017), 229 (), 110-114CODEN: BICIAZ; ISSN:0301-4622. (Elsevier B.V.)
  Far-UV CD expts. and Atomic Force Microscopy tomog. are employed to assess the impact of β-sheet breakers on the Aβ1-40 peptide aggregation process in the presence of Cu2+ or Zn2+ transition metals. In this work we focus on two specific 5-amino acids long β-sheet breakers, namely the LPFFD Soto peptide, already known in the literature, and the LPFFN peptide recently designed and studied by our team. We provide evidence that both β-sheet breakers are effective in reducing the Aβ1-40 aggregation propensity, even in the presence of metal ions.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotVCnsrs%253D&md5=7c1d59659d0ea3a89fc386f60f68fd97
40. 40
  Jensen, M.; Canning, A.; Chiha, S.; Bouquerel, P.; Pedersen, J. T.; Østergaard, J.; Cuvillier, O.; Sasaki, I.; Hureau, C.; Faller, P. Inhibition of Cu-Amyloid-β by Using Bifunctional Peptides with β-Sheet Breaker and Chelator Moieties. Chem. – Eur. J. 2012, 18, 4836– 4839, DOI: 10.1002/chem.201103546
  40
  Inhibition of Cu-Amyloid-β by using Bifunctional Peptides with β-Sheet Breaker and Chelator Moieties
  Jensen, Madeleine; Canning, Anne; Chiha, Sabri; Bouquerel, Pierre; Pedersen, Jeppe Trudslev; Ostergaard, Jesper; Cuvillier, Olivier; Sasaki, Isabelle; Hureau, Christelle; Faller, Peter
  Chemistry - A European Journal (2012), 18 (16), 4836-4839, S4836/1-S4836/4CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Herein, the authors present a dual approach to inhibit Aβ aggregation and ROS prodn. by combining two functions on a single peptide, i.e., the copper chelator and β-sheet breaker moieties. Inhibition of the formation of toxic Aβ aggregates (oligomers and others) and disruption of Cu-Aβ with subsequent redox-silencing of Cu have been considered promising strategies against Alzheimer's disease progression.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjvVWrtrw%253D&md5=6db2c7c1ca7fb3b0755ff7dda3878f1f
41. 41
  Rajasekhar, K.; Madhu, C.; Govindaraju, T. Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity. ACS Chem. Neurosci. 2016, 7, 1300– 1310, DOI: 10.1021/acschemneuro.6b00175
  41
  Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity
  Rajasekhar, K.; Madhu, Chilakapati; Govindaraju, T.
  ACS Chemical Neuroscience (2016), 7 (9), 1300-1310CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  Accumulation of amyloid beta (Aβ) peptide and its aggregates in the human brain is considered as one of the hallmarks of Alzheimer's disease (AD). The polymorphic oligomers and fully grown fibrillar aggregates of Aβ exhibit different levels of neuronal toxicity. Moreover, aggregation of Aβ in the presence of redox-active metal ions like Cu2+ is responsible for the addnl. trait of cellular toxicity induced by the generation of reactive oxygen species (ROS). Herein, a multifunctional peptidomimetic inhibitor (P6) has been presented, based on a naturally occurring metal chelating tripeptide (GHK) and the inhibitor of Aβ aggregation. It was shown by employing various biophys. studies that P6 interact with Aβ and prevent the formation of toxic Aβ forms like oligomeric species and fibrillar aggregates. Further, P6 successfully sequestered Cu2+ from the Aβ-Cu2+ complex and maintained it in a redox-dormant state to prevent the generation of ROS. P6 inhibited membrane disruption by Aβ oligomers and efficiently prevented DNA damage caused by the Aβ-Cu2+ complex. PC12 cells were rescued from multifaceted Aβ toxicity when treated with P6, and the amt. of ROS generated in cells was reduced. These attributes make P6 a potential therapeutic candidate to ameliorate the multifaceted Aβ toxicity in AD.
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42. 42
  Hu, X.; Zhang, Q.; Wang, W.; Yuan, Z.; Zhu, X.; Chen, B.; Chen, X. Tripeptide GGH as the Inhibitor of Copper-Amyloid-β-Mediated Redox Reaction and Toxicity. ACS Chem. Neurosci. 2016, 7, 1255– 1263, DOI: 10.1021/acschemneuro.6b00145
  42
  Tripeptide GGH as the Inhibitor of Copper-Amyloid-β-Mediated Redox Reaction and Toxicity
  Hu, Xiaoyu; Zhang, Qian; Wang, Wei; Yuan, Zhi; Zhu, Xushan; Chen, Bing; Chen, Xingyu
  ACS Chemical Neuroscience (2016), 7 (9), 1255-1263CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  The Aβ complexes of some redox-active species, such as Cu, cause oxidative stress and induce severe toxicity by generating reactive oxygen species (ROS). Thus, Cu chelation therapy should be considered as a valuable strategy for the treatment of Alzheimer's disease (AD). However, more attention should be paid to the specific chelating ability of these chelating agents. Herein, a tripeptide GGH was used to selectively chelate the Cu2+ in Aβ-Cu complex in the presence of other metal ions (e.g., K+, Ca2+, Ni2+, Mg2+, and Zn2+) as shown by isothermal titrn. calorimetry results. GGH decreased the level of HO• radicals by preventing the formation of intermediate Cu(I) ion. Thus, the Cu species completely lost its catalytic activity at a superequimolar GGH/Cu(II) ratio (4:1) as obsd. by UV-visible spectroscopy, coumarin-3-carboxylic acid fluorescence, and BCA assay. Moreover, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay indicates that GGH increased PC-12 cell viability from 36% to 63%, and neurotoxicity partly triggered by ROS decreased. These results indicate potential development of peptide chelation therapy for AD treatment.
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43. 43
  Rajasekhar, K.; Samanta, S.; Bagoband, V.; Murugan, N. A.; Govindaraju, T. Antioxidant Berberine-Derivative Inhibits Multifaceted Amyloid Toxicity. iScience 2020, 23, 101005, DOI: 10.1016/j.isci.2020.101005
  43
  Antioxidant Berberine-Derivative Inhibits Multifaceted Amyloid Toxicity
  Rajasekhar, Kolla; Samanta, Sourav; Bagoband, Vardhaman; Murugan, N. Arul; Govindaraju, Thimmaiah
  iScience (2020), 23 (4), 101005CODEN: ISCICE; ISSN:2589-0042. (Elsevier B.V.)
  Multiple lines of evidence indicate that amyloid beta (Aβ) peptide is responsible for the pathol. devastation caused in Alzheimer's disease (AD). Aβ aggregation species predominantly contribute to multifaceted toxicity obsd. in neuronal cells including generation of reactive oxygen species (ROS), mitochondrial dysfunction, interfering with synaptic signaling, and activation of premature apoptosis. Herein, we report a natural product berberine-derived (Ber-D) multifunctional inhibitor to ameliorate in cellulo multifaceted toxicity of AD. The structural attributes of polyphenolic Ber-D have contributed to its efficient Cu chelation and arresting the redox cycle to prevent the generation of ROS and rescue biomacromols. from oxidative damage. Ber-D inhibits metal-dependent and -independent Aβ aggregation, which is supported by in silico studies. Ber-D treatment averts mitochondrial dysfunction and corresponding neuronal toxicity contributing to premature apoptosis. These key multifunctional attributes make Ber-D a potential therapeutic candidate to ameliorate multifaceted Aβ toxicity in AD.
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44. 44
  Kim, M.; Kang, J.; Lee, M.; Han, J.; Nam, G.; Tak, E.; Kim, M. S.; Lee, H. J.; Nam, E.; Park, J.; Oh, S. J.; Lee, J.-Y.; Lee, J.-Y.; Baik, M.-H.; Lim, M. H. Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia. J. Am. Chem. Soc. 2020, 142, 8183– 8193, DOI: 10.1021/jacs.9b13100
  44
  Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia
  Kim, Mingeun; Kang, Juhye; Lee, Misun; Han, Jiyeon; Nam, Geewoo; Tak, Eunyoung; Kim, Min Sun; Lee, Hyuck Jin; Nam, Eunju; Park, Jiyong; Oh, Soo Jin; Lee, Ji-Yoon; Lee, Joo-Yong; Baik, Mu-Hyun; Lim, Mi Hee
  Journal of the American Chemical Society (2020), 142 (18), 8183-8193CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Multiple pathogenic elements, including reactive oxygen species, amyloidogenic proteins, and metal ions, are assocd. with the development of neurodegenerative disorders. We report minimalistic redox-based principles for prepg. compact arom. compds. by derivatizing the phenylene moiety with various functional groups. These mol. agents display enhanced reactivities against multiple targets such as free radicals, metal-free amyloid-β (Aβ), and metal-bound Aβ that are implicated in the most common form of dementia, Alzheimer's disease (AD). Mechanistic studies reveal that the redox properties of these reagents are essential for their function. Specifically, they engage in oxidative reactions with metal-free and metal-bound Aβ, leading to chem. modifications of the Aβ peptides to form covalent adducts that alter the aggregation of Aβ. Moreover, the administration of the most promising candidate significantly attenuates the amyloid pathol. in the brains of AD transgenic mice and improves their cognitive defects. Our studies demonstrate an efficient and effective redox-based strategy for incorporating multiple functions into simple mol. reagents.
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45. 45
  Samanta, S.; Rajasekhar, K.; Babagond, V.; Govindaraju, T. Small Molecule Inhibits Metal-Dependent and -Independent Multifaceted Toxicity of Alzheimer’s Disease. ACS Chem. Neurosci. 2019, 10, 3611– 3621, DOI: 10.1021/acschemneuro.9b00216
  45
  Small Molecule Inhibits Metal-Dependent and -Independent Multifaceted Toxicity of Alzheimer's Disease
  Samanta, Sourav; Rajasekhar, Kolla; Babagond, Vardhaman; Govindaraju, Thimmaiah
  ACS Chemical Neuroscience (2019), 10 (8), 3611-3621CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  Alzheimer's disease (AD) is one of the most devastating forms of dementia, without reliable treatments to cure, delay the onset of or prevent the disease progression. The proposed toxic mechanisms of AD include amyloidogenesis of amyloid β (Aβ), metal ions dyshomeostasis, redox active metal-Aβ inclusion complex formation and generation of excessive reactive oxygen and nitrogen species (ROS and RNS). The imbalance in redox homeostasis cause oxidative stress, DNA damage, mitochondrial dysfunction and inflammation, which collectively become a major hurdle in the development of effective therapeutic agents for multifactorial AD. This necessitates the need for a multifunctional strategy to develop effective therapeutic agents to inhibit multifaceted toxicity. In this context, we report a rational design, synthesis and detailed study to identify a small mol. multifunctional modulator (MFM) inspired by the human origin tripeptide. The lead MFM 4 chelates and sequester metal ions, disrupt their redox cycles and prevent excessive ROS prodn. and oxidative stress, ameliorate oxidative DNA damage and mitochondrial dysfunction, and modulate Nrf2 protein signaling under oxidative stress condition by eliminating the toxic stress elements. The MFM 4 was found to inhibit metal-dependent and independent Aβ aggregation and qualified as a suitable candidate to inhibit Aβ-induced neuronal toxicity. The NMR spectroscopy study revealed mol.-level interactions of 4 with Aβ42, which explain the mechanism of aggregation inhibition. Furthermore, 4 effectively inhibited the inflammation as revealed by redn. in nitric oxide (NO) prodn. in LPS-activated glial cells. These key features make 4 a potential MFM platform to develop therapeutic agents for metal (Cu, Zn and Fe)-dependent and independent multifaceted Aβ toxicity of AD.
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46. 46
  Stavchanskii, V. V.; Tvorogova, T. V.; Botsina, A. Y.; Limborska, S. A.; Skvortsova, V. I.; Myasoedov, N. F.; Dergunova, L. V. Effect of Peptide Semax and Its C-Terminal Fragment PGP on Vegfa Gene Expression during Incomplete Global Cerebral Ischemia in Rats. Mol. Biol. 2013, 47, 406– 410, DOI: 10.1134/S0026893313030151
  46
  Effect of peptide Semax and its C-terminal fragment PGP on Vegfa gene expression during incomplete global cerebral ischemia in rats
  Stavchanskii, V. V.; Tvorogova, T. V.; Botsina, A. Yu.; Limborska, S. A.; Skvortsova, V. I.; Myasoedov, N. F.; Dergunova, L. V.
  Molecular Biology (Moscow, Russian Federation, English Edition) (2013), 47 (3), 406-410CODEN: MOLBBJ; ISSN:0026-8933. (SP MAIK Nauka/Interperiodica)
  Vascular endothelial growth factor (VEGF-A) is hypoxia-inducible signal glycoprotein. VEGF-A induces vascular endothelial cell proliferation, which leads to the reconstitution of the vascular network in brain regions damaged by ischemia. However, this protein is also involved in the processes of inflammation and edema in early stages of ischemia. The synthetic peptide Semax has neuroprotective and anti-inflammatory properties and is actively used in the treatment of cerebral ischemia. We have previously shown that Semax reduces vascular injury and activates the mRNA synthesis of neurotrophins and their receptors during global cerebral ischemia in rats. In this work, we studied the effect of Semax and its C-terminal Pro-Gly-Pro tripeptide on Vegfa mRNA expression in different regions of the rat brain after 0.5, 1, 2, 4, 8, 12 and 24 h, which is the irreversible occlusion of the common carotid arteries. It was shown that ischemia increases the levels of Vegfa mRNA in rat brains (4 h after occlusion in cerebellum, cerebral cortex, and hippocampus; 8 h after occlusion in the cortex and hippocampus; and 24 h after occlusion in the cortex). Treatment with Semax reduces the levels of Vegfa mRNA in the frontal cortex (4, 8 and 12 h after occlusion) and the hippocampus (2 and 4 h after occlusion). The effect of PGP on the Vegfa gene expression was almost negligible. It was shown that Semax prevents the activating effect of hypoxia on the expression of the Vegfa gene at early stages of global cerebral ischemia. In turn, an increase in the level of Vegfa mRNA in the hippocampus 24 h after occlusion and Semax administration apparently reflects the neuroprotective properties of the drug.
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47. 47
  Bashkatova, V. G.; Koshelev, V. B.; Fadyukova, O. E.; Alexeev, A. A.; Vanin, A. F.; Rayevsky, K. S.; Ashmarin, I. P.; Armstrong, D. M. Novel Synthetic Analogue of ACTH 4–10 (Semax) but Not Glycine Prevents the Enhanced Nitric Oxide Generation in Cerebral Cortex of Rats with Incomplete Global Ischemia. Brain Res. 2001, 894, 145– 149, DOI: 10.1016/S0006-8993(00)03324-2
  47
  Novel synthetic analogue of ACTH 4-10 (Semax) but not glycine prevents the enhanced nitric oxide generation in cerebral cortex of rats with incomplete global ischemia
  Bashkatova, V. G.; Koshelev, V. B.; Fadyukova, O. E.; Alexeev, A. A.; Vanin, A. F.; Rayevsky, K. S.; Ashmarin, I. P.; Armstrong, D. M.
  Brain Research (2001), 894 (1), 145-149CODEN: BRREAP; ISSN:0006-8993. (Elsevier Science B.V.)
  This work investigates whether nitric oxide prodn. and lipid peroxidn. contribute to the pathophysiol. of ischemia and whether glycine and a novel Russian compd., Semax are neuroprotective via a mechanism involving the regulation nitric oxide (NO) and lipid peroxidn. In brief, nitric oxide and indexes of lipid peroxidn. were elevated following global ischemia. While glycine proved ineffective in reducing NO levels or ameliorating the neurol. deficits following global ischemia, Semax proved to be highly effective in abating the rise in nitric oxide and restoring neurol. functioning.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhs1eitL8%253D&md5=db6b9f76764b3cd156a4cdce75c69a6a
48. 48
  Potaman, V. N.; Antonova, L. V.; Dubynin, V. A.; Zaitzev, D. A.; Kamensky, A. A.; Myasoedov, N. F.; Nezavibatko, V. N. Entry of the Synthetic ACTH(4–10) Analogue into the Rat Brain Following Intravenous Injection. Neurosci. Lett. 1991, 127, 133– 136, DOI: 10.1016/0304-3940(91)90912-D
  48
  Entry of the synthetic ACTH(4-10) analog into the rat brain following intravenous injection
  Potaman, V. N.; Antonova, L. V.; Dubynin, V. A.; Zaitsev, D. A.; Kamenskii, A. A.; Myasoedov, N. F.; Nezavibat'ko, V. N.
  Neuroscience Letters (1991), 127 (1), 133-6CODEN: NELED5; ISSN:0304-3940.
  In view of known central effects of N-terminal ACTH fragments, a possibility of their entry into the brain was studied. Rat blood and brain exts. after i.v. injection of the tritiated synthetic ACTH(4-10) analog, Met-Glu-His-Phe-Gly-Pro, were subjected to an HPLC anal. At two time points the labeled peptide was detected in brain exts. The brain to blood ratios of peptide content in brain and blood were found to be significantly higher than those calcd. for a distribution of labeled bovine serum albumin in rat brain capillaries and blood. This strongly suggests that this peptide penetrates into the brain tissues, its quantity not exceeding 0.01% of dose injected. Peptide diffusion through the vascular epithelium of brain capillaries could account for the data obtained.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXlvFyqtrg%253D&md5=827bae7bfc9b13df50a77f299256a842
49. 49
  Kolomin, T.; Shadrina, M.; Slominsky, P.; Limborska, S.; Myasoedov, N. A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides. Neurosci. Med. 2013, 04, 720– 252, DOI: 10.4236/nm.2013.44035
  There is no corresponding record for this reference.
50. 50
  Storozhevykh, T. P.; Tukhbatova, G. R.; Senilova, Y. E.; Pinelis, V. G.; Andreeva, L. A.; Myasoyedov, N. F. Effects of Semax and Its Pro-Gly-Pro Fragment on Calcium Homeostasis of Neurons and Their Survival under Conditions of Glutamate Toxicity. Bull. Exp. Biol. Med. 2007, 143, 601– 604, DOI: 10.1007/s10517-007-0192-x
  50
  Effects of semax and its Pro-Gly-Pro fragment on calcium homeostasis of neurons and their survival under conditions of glutamate toxicity
  Storozhevykh, T. P.; Tukhbatova, G. R.; Senilova, Ya. E.; Pinelis, V. G.; Andreeva, L. A.; Myasoyedov, N. F.
  Bulletin of Experimental Biology and Medicine (2007), 143 (5), 601-604CODEN: BEXBAN; ISSN:0007-4888. (Springer)
  Semax (100 μM) and its Pro-Gly-Pro fragment (20 and 100 μM) delayed the development of calcium dysregulation and redn. of the mitochondrial potential in cultured cerebellar granule cells under conditions of glutamate neurotoxicity. Incubation with these peptides improved neuronal survival by on av. 30%. The neuroprotective effect of semax in cerebral ischemia/hypoxia can be due to improvement of mitochondrial resistance to "calcium" stress.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFSlsrbN&md5=3916e3efe4ccc5ad21d3517360cb74ac
51. 51
  Ashmarin, I. P.; Nezavibatko, V. N.; Levitskaya, N. G.; Koshelev, V. B.; Kamensky, A. A. Design and Investigation of an ACTH(4-10) Analogue Lacking D-Amino Acids and Hydrophobic Radicals. Neurosci. Res. Commun. 1995, 16, 105– 112
  51
  Design and investigation of an ACTH(4-10) analog-lacking D-amino acids and hydrophobic radicals
  Ashmarin, I. P.; Nezavibatko, V. N.; Levitskaya, N. G.; Koshelev, V. B.; Kamensky, A. A.
  Neuroscience Research Communications (1995), 16 (2), 105-12CODEN: NRCOEE; ISSN:0893-6609.
  The biol. activity of an ACTH(4-10) analog, Semax (MEHFPGP), has been studied. This peptide was shown to have a beneficial effect on the functions of the central nervous system. Semax accelerated the learning process in animals and had a prolonged effect in comparison to ACTH(4-10). It increased the resistance of rats exposed to hypobaric and circulatory hypoxia. Semax had a protective effect against the development of hemorrhagic stroke in rats. The data obtained underscore the potential of Semax as a stimulator of memory and mental functions and as a potential antihypoxic and antistroke drug.
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52. 52
  Kaplan, A. Y.; Kochetova, A. G.; Nezavibathko, V. N.; Rjasina, T. V.; Ashmarin, I. P. Synthetic ACTH Analogue Semax Displays Nootropic-like Activity in Humans. Neurosci. Res. Commun. 1996, 19, 115– 123, DOI: 10.1002/(SICI)1520-6769(199609)19:2<115::AID-NRC171>3.0.CO;2-B
  52
  Synthetic ACTH analog Semax displays nootropic-like activity in humans
  Kaplan, A. Ya.; Kochetova, A. G.; Nezavibathko, V. N.; Rjasina, T. V.; Ashmarion, I. P.
  Neuroscience Research Communications (1996), 19 (2), 115-123CODEN: NRCOEE; ISSN:0893-6609. (Wiley)
  Nootropic properties of the ACTH(4-10) analog Semax were demonstrated in expts. with human volunteers. The antihypoxic effect of Semax was shown by EEG anal. after short-term hyperventilation. Semax induced changes in the EEG similar to those seen after administration of typical nootropic drugs. Particularly important was the long-term (20-24 h) beneficial action of Semax on the work efficiency of operators after intranasal administration of 0.25-1.0 mg of the peptide (about 4.0-16.0 μg/kg body wt.).
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53. 53
  Dolotov, O. V.; Karpenko, E. A.; Seredenina, T. S.; Inozemtseva, L. S.; Levitskaya, N. G.; Zolotarev, Y. A.; Kamensky, A. A.; Grivennikov, I. A.; Engele, J.; Myasoedov, N. F. Semax, an Analogue of Adrenocorticotropin (4–10), Binds Specifically and Increases Levels of Brain-Derived Neurotrophic Factor Protein in Rat Basal Forebrain. J. Neurochem. 2006, 97, 82– 86, DOI: 10.1111/j.1471-4159.2006.03658.x
  53
  Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain
  Dolotov, Oleg V.; Karpenko, Ekaterina A.; Seredenina, Tamara S.; Inozemtseva, Lyudmila S.; Levitskaya, Natalia G.; Zolotarev, Yuriy A.; Kamensky, Andrey A.; Grivennikov, Igor A.; Engele, Juergen; Myasoedov, Nikolay F.
  Journal of Neurochemistry (2006), 97 (Suppl. 1), 82-86CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)
  The heptapeptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) is an analog of the N-terminal fragment (4-10) of adrenocorticotropic hormone which, after intranasal application, has profound effects on learning and memory formation in rodents and humans, and also exerts marked neuroprotective effects. A clue to the mol. mechanism underlying this neurotropic action was recently given by the observation that Semax stimulates the synthesis of brain-derived neurotrophic factor (BDNF), a potent modulator of synaptic plasticity, in astrocytes cultured from rat basal forebrain. In the present study, the authors investigated whether Semax affects BDNF levels in rat basal forebrain upon intranasal application of the peptide. In addn., the authors examd. whether cell membranes isolated from this brain region contained binding sites for Semax. The binding of tritium-labeled Semax was found to be time dependent, specific and reversible. Specific Semax binding required calcium ions and was characterized by a mean ± SEM dissocn. const. (KD) of 2.4±1.0 nM and a BMAX value of 33.5±7.9 fmol/mg protein. Sandwich immunoenzymic anal. revealed that Semax applied intranasally at 50 and 250 μg/kg bodyweight resulted in a rapid increase in BDNF levels after 3 h in the basal forebrain, but not in the cerebellum. These results point to the presence of specific binding sites for Semax in the rat basal forebrain. In addn., these findings indicate that the cognitive effects exerted by Semax might be assocd., at least in part, with increased BDNF protein levels in this brain region.
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54. 54
  Dolotov, O. V.; Karpenko, E. A.; Inozemtseva, L. S.; Seredenina, T. S.; Levitskaya, N. G.; Rozyczka, J.; Dubynina, E. V.; Novosadova, E. V.; Andreeva, L. A.; Alfeeva, L. Y.; Kamensky, A. A.; Grivennikov, I. A.; Myasoedov, N. F.; Engele, J. Semax, an Analog of ACTH(4–10) with Cognitive Effects, Regulates BDNF and TrkB Expression in the Rat Hippocampus. Brain Res. 2006, 1117, 54– 60, DOI: 10.1016/j.brainres.2006.07.108
  54
  Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus
  Dolotov, Oleg V.; Karpenko, Ekaterina A.; Inozemtseva, Lyudmila S.; Seredenina, Tamara S.; Levitskaya, Natalia G.; Rozyczka, Joanna; Dubynina, Elena V.; Novosadova, Ekaterina V.; Andreeva, Lyudmila A.; Alfeeva, Lyudmila Yu.; Kamensky, Andrey A.; Grivennikov, Igor A.; Myasoedov, Nikolay F.; Engele, Juergen
  Brain Research (2006), 1117 (1), 54-60CODEN: BRREAP; ISSN:0006-8993. (Elsevier Ltd.)
  The heptapeptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) is an analog of the ACTH fragment (4-10) which after intranasal application has profound effects on learning and exerts marked neuroprotective activities. Here, we found that a single application of Semax (50 μg/kg body wt.) results in a maximal 1.4-fold increase of BDNF protein levels accompanying with 1.6-fold increase of trkB tyrosine phosphorylation levels, and a 3-fold and a 2-fold increase of exon III BDNF and trkB mRNA levels, resp., in the rat hippocampus. Semax-treated animals showed a distinct increase in the no. of conditioned avoidance reactions. We suggest that Semax affects cognitive brain functions by modulating the expression and the activation of the hippocampal BDNF/trkB system.
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55. 55
  Tabbì, G.; Magrì, A.; Giuffrida, A.; Lanza, V.; Pappalardo, G.; Naletova, I.; Nicoletti, V. G.; Attanasio, F.; Rizzarelli, E. Semax, an ACTH4-10 Peptide Analog with High Affinity for Copper(II) Ion and Protective Ability against Metal Induced Cell Toxicity. J. Inorg. Biochem. 2015, 142, 39– 46, DOI: 10.1016/j.jinorgbio.2014.09.008
  55
  Semax, an ACTH4-10 peptide analog with high affinity for copper(II) ion and protective ability against metal induced cell toxicity
  Tabbi, Giovanni; Magri, Antonio; Giuffrida, Alessandro; Lanza, Valeria; Pappalardo, Giuseppe; Naletova, Irina; Nicoletti, Vincenzo Giuseppe; Attanasio, Francesco; Rizzarelli, Enrico
  Journal of Inorganic Biochemistry (2015), 142 (), 39-46CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
  Heptapeptide Semax, encompassing the sequence 4-7 of N-terminal domain of the adrenocorticotropic hormone (ACTH) and a C-terminal Pro-Gly-Pro tripeptide, belongs to a short regulatory peptides family. This compd. has been found to affect learning processes and to exert marked neuroprotective activities on cognitive brain functions. Dys-homeostasis of metal ions is involved in several neurodegenerative disorders and growing evidences have showed that brain is a specialized organ able to conc. metal ions. In this work, the metal binding ability and protective activity of Semax and its metal complexes were studied. The equil. study clearly demonstrated the presence of three complex species. Two minor species [CuL] and [CuLH-1]- co-exist together with the [CuLH-2]2- in the pH range from 3.6 to 5. From pH 5 the [CuLH-2]2- species becomes predominant with the donor atoms around copper arranged in a 4 N planar coordination mode. Noteworthy, a reduced copper induced cytotoxicity was obsd. in the presence of Semax by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay on a SHSY5Y neuroblastoma and RBE4 endothelial cell lines.
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56. 56
  Magrì, A.; Tabbì, G.; Giuffrida, A.; Pappalardo, G.; Satriano, C.; Naletova, I.; Nicoletti, V. G.; Attanasio, F. Influence of the N-Terminus Acetylation of Semax, a Synthetic Analog of ACTH(4-10), on Copper(II) and Zinc(II) Coordination and Biological Properties. J. Inorg. Biochem. 2016, 164, 59– 69, DOI: 10.1016/j.jinorgbio.2016.08.013
  56
  Influence of the N-terminus acetylation of Semax, a synthetic analog of ACTH(4-10), on copper(II) and zinc(II) coordination and biological properties
  Magri, Antonio; Tabbi, Giovanni; Giuffrida, Alessandro; Pappalardo, Giuseppe; Satriano, Cristina; Naletova, Irina; Nicoletti, Vincenzo G.; Attanasio, Francesco
  Journal of Inorganic Biochemistry (2016), 164 (), 59-69CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
  Semax is a heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro) that encompasses the sequence 4-7 of N-terminal domain of the adrenocorticotropic hormone and a C-terminal Pro-Gly-Pro tripeptide. N-terminal amino group acetylation (Ac-Semax) modulates the chem. and biol. properties of parental peptide, modifying the ability of Semax to form complex species with Cu(II) ion. At physiol. pH, the main complex species formed by Ac-Semax, [CuLH-2]2-, consists in a distorted CuN3O chromophore with a weak apical interaction of the methionine sulfur. Such a complex differs from the Cu(II)-Semax complex system, which exhibits a CuN4 chromophore. The reduced ligand field affects the [CuLH-2]2- formal redox potential, which is more pos. than that of Cu(II)-Semax corresponding species. In the amino-free form, the resulting complex species is redox-stable and unreactive against ascorbic acid, unlike the acetylated form. Semax acetylation did not protect from Cu(II) induced toxicity on a SH-SY5Y neuroblastoma cell line, thus demonstrating the crucial role played by the free NH2 terminus in the cell protection. Since several brain diseases are assocd. either to Cu(II) or Zn(II) dyshomeostasis, here we characterized also the complex species formed by Zn(II) with Semax and Ac-Semax. Both peptides were able to form Zn(II) complex species with comparable strength. Confocal microscopy imaging confirmed that peptide group acetylation does not affect the Zn(II) influx in neuroblastoma cells. Moreover, a punctuate distribution of Zn(II) within the cells suggests a preferred subcellular localization that might explain the zinc toxic effect. A future perspective can be the use of Ac-Semax as ionophore in antibody drug conjugates to produce a dysmetallostasis in tumor cells.
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57. 57
  Gade Malmos, K.; Blancas-Mejia, L. M.; Weber, B.; Buchner, J.; Ramirez-Alvarado, M.; Naiki, H.; Otzen, D. ThT 101: A Primer on the Use of Thioflavin T to Investigate Amyloid Formation. Amyloid 2017, 24, 1– 16, DOI: 10.1080/13506129.2017.1304905
  57
  ThT 101: a primer on the use of thioflavin T to investigate amyloid formation
  Gade Malmos, Kirsten; Blancas-Mejia, Luis M.; Weber, Benedikt; Buchner, Johannes; Ramirez-Alvarado, Marina; Naiki, Hironobu; Otzen, Daniel
  Amyloid (2017), 24 (1), 1-16CODEN: AIJIET; ISSN:1350-6129. (Taylor & Francis Ltd.)
  Thioflavin T (ThT) has been widely used to investigate amyloid formation since 1989. While concerns have recently been raised about its use as a probe specific for amyloid, ThT still continues to be a very valuable tool for studying kinetic aspects of fibrillation and assocd. inhibition mechanisms. This review aims to provide a conceptual instruction manual, covering appropriate considerations and pitfalls related to the use of ThT. We start by giving a brief introduction to amyloid formation with focus on the morphol. of different aggregate species, followed by a discussion of the quality of protein needed to obtain reliable fibrillation data. After an overview of the photochem. basis for ThT's amyloid binding properties and artifacts that may arise from this, we describe how to plan and analyze ThT assays. We conclude with recommendations for complementary techniques to address shortcomings in the ThT assay.
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58. 58
  Dorlet, P.; Gambarelli, S.; Faller, P.; Hureau, C. Pulse EPR Spectroscopy Reveals the Coordination Sphere of Copper(II) Ions in the 1–16 Amyloid-β Peptide: A Key Role of the First Two N-Terminus Residues. Angew. Chem., Int. Ed. 2009, 48, 9273– 9276, DOI: 10.1002/anie.200904567
  58
  Pulse EPR Spectroscopy Reveals the Coordination Sphere of Copper(II) Ions in the 1-16 Amyloid-β Peptide: A Key Role of the First Two N-Terminus Residues
  Dorlet, Pierre; Gambarelli, Serge; Faller, Peter; Hureau, Christelle
  Angewandte Chemie, International Edition (2009), 48 (49), 9273-9276, S9273/1-S9273/14CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The authors used a wide range of EPR methods, including continuous wave, ESEEM, 4-pulse HYSCORE, and pulse ENDOR and 6-pulse HYSCORE, combined with specific isotopic labeling to study CuII-Aβ1-16 (DAEFRHDSGYEVHHQK). The unambiguous identification of the CuII ligands in components I and II achieved in this study underlines the key role of residues D1 and A2 in the coordination of the metal ion.
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59. 59
  Sarell, C. J.; Syme, C. D.; Rigby, S. E. J.; Viles, J. H. Copper(II) Binding to Amyloid-β Fibrils of Alzheimer’s Disease Reveals a Picomolar Affinity: Stoichiometry and Coordination Geometry Are Independent of Aβ Oligomeric Form. Biochemistry 2009, 48, 4388– 4402, DOI: 10.1021/bi900254n
  59
  Copper(II) Binding to Amyloid-β Fibrils of Alzheimer's Disease Reveals a Picomolar Affinity: Stoichiometry and Coordination Geometry Are Independent of Aβ Oligomeric Form
  Sarell, Claire J.; Syme, Christopher D.; Rigby, Stephen E. J.; Viles, John H.
  Biochemistry (2009), 48 (20), 4388-4402CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  Cu2+ ions are found concd. within senile plaques of Alzheimer's disease patients directly bound to amyloid-β peptide (Aβ) and are linked to the neurotoxicity and self-assocn. of Aβ. The affinity of Cu2+ for monomeric Aβ is highly disputed, and there have been no reports of affinity of Cu2+ for fibrillar Aβ. We therefore measured the affinity of Cu2+ for both monomeric and fibrillar Aβ(1-42) using two independent methods: fluorescence quenching and CD. The binding curves were almost identical for both fibrillar and monomeric forms. Competition studies with free glycine, L-histidine, and nitrilotriacetic acid (NTA) indicate an apparent (conditional) dissocn. const. of 10-11 M, at pH 7.4. Previous studies of Cu-Aβ have typically found the affinity 2 or more orders of magnitude weaker, largely because the affinity of competing ligands or buffers has been underestimated. Aβ fibers are able to bind a full stoichiometric complement of Cu2+ ions with little change in their secondary structure and have coordination geometry identical to that of monomeric Aβ. ESR studies (EPR) with Aβ His/Ala analogs suggest a dynamic view of the tetragonal Cu2+ complex, with axial as well as equatorial coordination of imidazole nitrogens creating an ensemble of coordination geometries in exchange between each other. Furthermore, the N-terminal amino group is essential for the formation of high-pH complex II. The Aβ(1-28) fragment binds an addnl. Cu2+ ion compared to full-length Aβ, with appreciable affinity. This second binding site is revealed in Aβ(1-42) upon addn. of methanol, indicating hydrophobic interactions block the formation of this weaker carboxylate-rich complex. A Cu2+ affinity for Aβ of 1011 M-1 supports a modified amyloid cascade hypothesis in which Cu2+ is central to Aβ neurotoxicity.
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60. 60
  Faller, P.; Hureau, C.; Berthoumieu, O. Role of Metal Ions in the Self-Assembly of the Alzheimer’s Amyloid-β Peptide. Inorg. Chem. 2013, 52, 12193– 12206, DOI: 10.1021/ic4003059
  60
  Role of Metal Ions in the Self-assembly of the Alzheimer's Amyloid-β Peptide
  Faller, Peter; Hureau, Christelle; Berthoumieu, Olivia
  Inorganic Chemistry (2013), 52 (21), 12193-12206CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
  A review. Aggregation of amyloid-β (Aβ) by self-assembly into oligomers or amyloids is a central event in Alzheimer's disease. Coordination of transition-metal ions, mainly copper and zinc, to Aβ occurs in vivo and modulates the aggregation process. A survey of the impact of CuII and ZnII on the aggregation of Aβ reveals some general trends: (i) ZnII and CuII at high micromolar concns. and/or in a large superstoichiometric ratio compared to Aβ have a tendency to promote amorphous aggregations (pptn.) over the ordered formation of fibrillar amyloids by self-assembly; (ii) metal ions affect the kinetics of Aβ aggregations, with the most significant impact on the nucleation phase; (iii) the impact is metal-specific; (iv) CuII and ZnII affect the concns. and/or the types of aggregation intermediates formed; (v) the binding of metal ions changes both the structure and the charge of Aβ. The decrease in the overall charge at physiol. pH increases the overall driving force for aggregation but may favor more pptn. over fibrillation, whereas the induced structural changes seem more relevant for the amyloid formation.
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61. 61
  Sarell, C. J.; Wilkinson, S. R.; Viles, J. H. Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease. J. Biol. Chem. 2010, 285, 41533– 41540, DOI: 10.1074/jbc.M110.171355
  61
  Substoichiometric levels of Cu2+ ions Accelerate the kinetics of fiber formation and promote cell toxicity of amyloid-β from Alzheimer disease
  Sarell, Claire J.; Wilkinson, Shane R.; Viles, John H.
  Journal of Biological Chemistry (2010), 285 (53), 41533-41540CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
  A role for Cu2+ ions in Alzheimer disease is often disputed, as it is believed that Cu2+ ions only promote nontoxic amorphous aggregates of amyloid-β (Aβ). In contrast with currently held opinion, we show that the presence of substoichiometric levels of Cu2+ ions in fact doubles the rate of prodn. of amyloid fibers, accelerating both the nucleation and elongation of fiber formation. We suggest that binding of Cu2+ ions at a physiol. pH causes Aβ to approach its isoelec. point, thus inducing self-assocn. and fiber formation. We further show that Cu2+ ions bound to Aβ are consistently more toxic to neuronal cells than Aβ in the absence of Cu2+ ions, whereas Cu2+ ions in the absence of Aβ are not cytotoxic. The degree of Cu-Aβ cytotoxicity correlates with the levels of Cu2+ ions that accelerate fiber formation. We note the effect appears to be specific for Cu2+ ions as Zn2+ ions inhibit the formation of fibers. An active role for Cu2+ ions in accelerating fiber formation and promoting cell death suggests impaired copper homeostasis may be a risk factor in Alzheimer disease.
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62. 62
  Zhang, Q.; Hu, X.; Wang, W.; Yuan, Z. Study of a Bifunctional Aβ Aggregation Inhibitor with the Abilities of Antiamyloid-β and Copper Chelation. Biomacromolecules 2016, 17, 661– 668, DOI: 10.1021/acs.biomac.5b01603
  62
  Study of a Bifunctional Aβ Aggregation Inhibitor with the Abilities of Antiamyloid-β and Copper Chelation
  Zhang, Qian; Hu, Xiaoyu; Wang, Wei; Yuan, Zhi
  Biomacromolecules (2016), 17 (2), 661-668CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
  In this study, a bifunctional Aβ aggregation inhibitor peptide, GGHRYYAAFFARR (GR), with the abilities to bind copper and antiamyloid was designed to inhibit the neurotoxicity of the Aβ-Cu(II) complex. The thioflavin T (ThT) assay, turbidimetric anal., transmission electron microscopy (TEM), and (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay were used to study its potential inhibitory effect on Aβ aggregation. Our findings indicate that GGH was the specific chelating sequence and that the RYYAAFFARR (RR) component acted as an aggregation inhibitor. More importantly, GR significantly decreased the cytotoxicity of the Aβ-Cu(II) complex. The cell viability improved to 88%, which was higher than with the single functional peptide GGH and RR by 39% and 20%, resp. Moreover, the qual. effect of Cu(II) on the Aβ-Cu(II) complex was also studied. Our results indicate that Cu(II) induces the formation of the β-sheet structure with a subequimolar Cu(II):Aβ molar ratio (0.25:1) but led to increased ROS prodn. at a supra-equimolar ratio.
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63. 63
  Faller, P.; Hureau, C. Bioinorganic Chemistry of Copper and Zinc Ions Coordinated to Amyloid-β Peptide. Dalton Trans. 2009, 7, 1080– 1094, DOI: 10.1039/B813398K
  There is no corresponding record for this reference.
64. 64
  Tõugu, V.; Karafin, A.; Palumaa, P. Binding of Zinc(II) and Copper(II) to the Full-Length Alzheimer’s Amyloid-Beta Peptide. J. Neurochem. 2008, 104, 1249– 1259, DOI: 10.1111/j.1471-4159.2007.05061.x
  64
  Binding of zinc(II) and copper(II) to the full-length Alzheimer's amyloid-β peptide
  Tougu, Vello; Karafin, Ann; Palumaa, Peep
  Journal of Neurochemistry (2008), 104 (5), 1249-1259CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)
  There is evidence that binding of metal ions like Zn2+ and Cu2+ to amyloid beta-peptides (Aβ) may contribute to the pathogenesis of Alzheimer's disease (AD). Cu2+ and Zn2+ form complexes with Aβ peptides in vitro; however, the published metal-binding affinities of Aβ vary in an enormously large range. We studied the interactions of Cu2+ and Zn2+ with monomeric Aβ40 under different conditions using intrinsic Aβ fluorescence and metal-selective fluorescent dyes. We showed that Cu2+ forms a stable and sol. 1: 1 complex with Aβ40; however, buffer compds. act as competitive copper-binding ligands and affect the apparent KD. Buffer-independent conditional KD for Cu(II)-Aβ40 complex at pH 7.4 is equal to 0.035 μmol/L. Interaction of Aβ40 with Zn2+ is more complicated, as partial aggregation of the peptide occurs during zinc titrn. expt. and in the same time period (within 30 min) the initial Zn-Aβ40 complex (KD = 60 μmol/L) undergoes a transition to a more tight complex with KD ∼ 2 μmol/L. Competition of Aβ40 with ion-selective fluorescent dyes Phen Green and Zincon showed that the KD values detd. from intrinsic fluorescence of Aβ correspond to the binding of the first Cu2+ and Zn2+ ions to the peptide with the highest affinity. Interaction of both Zn2+ and Cu2+ ions with Aβ peptides may occur in brain areas affected by Alzheimer's disease and Zn2+-induced transition in the peptide structure might contribute to amyloid plaque formation.
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65. 65
  Alies, B.; Renaglia, E.; Rózga, M.; Bal, W.; Faller, P.; Hureau, C. Cu(II) Affinity for the Alzheimer’s Peptide: Tyrosine Fluorescence Studies Revisited. Anal. Chem. 2013, 85, 1501– 1508, DOI: 10.1021/ac302629u
  65
  Cu(II) Affinity for the Alzheimer's Peptide: Tyrosine Fluorescence Studies Revisited
  Alies, Bruno; Renaglia, Emelyne; Rozga, Malgorzata; Bal, Wojciech; Faller, Peter; Hureau, Christelle
  Analytical Chemistry (Washington, DC, United States) (2013), 85 (3), 1501-1508CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  Copper(II) binding to the amyloid-β peptide has been proposed to be a key event in the cascade leading to Alzheimer's disease. As a direct consequence, the strength of the Cu(II) to Aβ interaction, i.e., the Cu(II) affinity of Aβ, is a very important parameter to det. Because Aβ peptide contain one Tyr fluorophore in its sequence and because Cu(II) does quench Tyr fluorescence, fluorescence measurements appear to be a straightforward way to obtain this parameter. However, this proved to be wrong, mainly because of data misinterpretation in some previous studies that lead to a conflicting situation. In the present paper, we have investigated in details a large set of fluorescence data that were analyzed with a new method taking into account the presence of two Cu(II) sites and the inner-filter effect. This leads to reinterpretation of the published data and to the detn. of a unified affinity value in the 1010 M-1 range.
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66. 66
  Young, T. R.; Kirchner, A.; Wedd, A. G.; Xiao, Z. An Integrated Study of the Affinities of the Aβ16 Peptide for Cu(I) and Cu(II): Implications for the Catalytic Production of Reactive Oxygen Species. Metallomics 2014, 6, 505– 517, DOI: 10.1039/C4MT00001C
  66
  An integrated study of the affinities of the Aβ16 peptide for Cu(i) and Cu(ii): implications for the catalytic production of reactive oxygen species
  Young, Tessa R.; Kirchner, Angie; Wedd, Anthony G.; Xiao, Zhiguang
  Metallomics (2014), 6 (3), 505-517CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
  A new fluorescent probe Aβ16wwa based upon the Aβ16 peptide has been developed with two orders of magnitude greater fluorescence intensity for sensitive detection of interactions with Cu(ii). In combination with the Cu(i) probe Ferene S, it is confirmed that the Aβ16 peptide binds either Cu(i) or Cu(ii) with comparable affinities at pH 7.4 (log KID = -10.4; log KIID = -10.0). It follows from this property that the Cu-Aβ16 complex is a robust if slow catalyst for the aerial oxidn. of ascorbate with H2O2 as primary product (initial rate, ∼0.63 min-1 for Cu-Aβ16 vs. >2.5 min-1 for Cuaq2+). An integrated study of variants of this peptide identifies the major ligands and binding modes involved in its copper complexes in soln. The dependence of KID upon pH is consistent with a two-coordinate Cu(i) site in which dynamic processes exchange Cu(i) between the three available pairs of imidazole sidechains provided by His6, His13 and His14. The N-terminal amine is not involved in Cu(i) binding but is a key ligand for Cu(ii). Acetylation of the N-terminus alters the redox thermodn. gradient for the Cu center and suppresses its catalytic activity considerably. The data indicate the presence of dynamic processes that exchange Cu(ii) between the three His ligands and backbone amide at physiol. pH. His6 is identified as a key ligand for catalysis as its presence minimizes the pre-organization energy required for interchange of the two copper redox sites. These new thermodn. data strengthen structural interpretations for the Cu-Aβ complexes and provide valuable insights into the mol. mechanism by which copper chem. may induce oxidative stress in Alzheimer's disease.
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67. 67
  Jongbloed, W.; van Dijk, K. D.; Mulder, S. D.; van de Berg, W. D. J.; Blankenstein, M. A.; van der Flier, W.; Veerhuis, R. Clusterin Levels in Plasma Predict Cognitive Decline and Progression to Alzheimer’s Disease. J. Alzheimer’s Dis. 2015, 46, 1103– 1110, DOI: 10.3233/JAD-150036
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  Clusterin Levels in Plasma Predict Cognitive Decline and Progression to Alzheimer's Disease
  Jongbloed, Wesley; van Dijk, Karin D.; Mulder, Sandra D.; van de Berg, Wilma D. J.; Blankenstein, Marinus A.; van der Flier, Wiesje; Veerhuis, Robert; Nielsen, Henrietta
  Journal of Alzheimer's Disease (2015), 46 (4), 1103-1110CODEN: JADIF9; ISSN:1387-2877. (IOS Press)
  Background: Increased clusterin levels have been reported in brain, cerebrospinal fluid (CSF), and plasma of Alzheimer's disease (AD) patients. Because changes are also obsd. in mild cognitive impairment (MCI), a possible relationship between clusterin levels and early neurodegenerative changes in AD was suggested. Objectives: To det. whether clusterin concns. could 1. serve as a diagnostic marker for AD, 2. predict disease progression in MCI, and 3. correlate with AD-biomarkers. Methods: Clusterin levels in CSF and plasma, as well as AD biomarker levels of Aβ 42, Tau, and pTau in CSF and Mini-Mental State Examn. scores (MMSE) were detd. in 67 controls, 50 MCI, and 107 AD patients. Repeated MMSE was obtained for 44 MCI and 72 AD patients after, on av., 2.7 years. Results: Elevated clusterin concns. in plasma, but not in CSF, were a risk factor for AD (HR 18.6; 95% CI 2.8-122), and related to cognitive decline in MCI (r=-0.38; p< 0.01). An inverse relation between plasma clusterin levels and cognitive decline was obsd. in AD patients (r=0.23; p≤0.05). In CSF, but not in plasma, clusterin levels correlated with Tau and pTau in all groups. Conclusion: Elevated plasma clusterin levels in MCI confer an increased risk for progression to AD, and more rapid cognitive decline. We speculate that clusterin levels in CSF may reflect its involvement in the earliest neurodegenerative processes assocd. with AD pathol. Whereas neither clusterin levels in CSF nor in plasma had diagnostic value, plasma clusterin levels may serve as a prognostic marker for AD.
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68. 68
  Banerjee, S.; Lyubchenko, Y. L. Interaction of Amyloidogenic Proteins with Membranes and Molecular Mechanism for the Development of Alzheimer’s Disease. Alzheimer’s Res. Ther. Open Access 2019, 2, 106
  There is no corresponding record for this reference.
69. 69
  Kakio, A.; Nishimoto, S.; Yanagisawa, K.; Kozutsumi, Y.; Matsuzaki, K. Interactions of Amyloid Beta-Protein with Various Gangliosides in Raft-like Membranes: Importance of GM1 Ganglioside-Bound Form as an Endogenous Seed for Alzheimer Amyloid. Biochemistry 2002, 41, 7385– 7390, DOI: 10.1021/bi0255874
  69
  Interactions of amyloid β-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid
  Kakio, Atsuko; Nishimoto, Seiichi; Yanagisawa, Katsuhiko; Kozutsumi, Yasunori; Matsuzaki, Katsumi
  Biochemistry (2002), 41 (23), 7385-7390CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  GM1 ganglioside-bound amyloid β-protein (GM1-Aβ), found in brains exhibiting early pathol. changes of Alzheimer's disease (AD) plaques, has been suggested to accelerate amyloid fibril formation by acting as a seed. We have previously found using dye-labeled Aβ that Aβ recognizes a GM1 cluster, the formation of which is facilitated by cholesterol. In this study, we investigated the ganglioside species-specificity in its potency to induce a conformational change of Aβ, by which ganglioside-bound Aβ acts as a seed for Aβ fibrillogenesis, using a major ganglioside occurring in brains (GM1, GD1a, GD1b, and GT1b) in raft-like membranes composed of cholesterol and sphingomyelin. Aβ recognized ganglioside clusters, the d. of which increased with the no. of sialic acid residues. Interestingly, however, mixing of gangliosides inhibited cluster formation. In contrast, the affinities of the protein for the clusters were similar irresp. of lipid compn. and were of the order of 106 M-1 at 37°. Aβ underwent a conformational transition from an α-helix-rich structure to a β-sheet-rich structure with the increase in protein d. on the membrane. Ganglioside-bound Aβ proteins exhibited seeding abilities for amyloid formation. GM1-Aβ exhibited the strongest seeding potential, esp. under β-sheet-forming conditions. This study suggested that lipid compn. including gangliosides and cholesterol strictly controls amyloid formation.
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70. 70
  Sasahara, K.; Morigaki, K.; Shinya, K. Effects of Membrane Interaction and Aggregation of Amyloid β-Peptide on Lipid Mobility and Membrane Domain Structure. Phys. Chem. Chem. Phys. 2013, 15, 8929– 8939, DOI: 10.1039/c3cp44517h
  70
  Effects of membrane interaction and aggregation of amyloid β-peptide on lipid mobility and membrane domain structure
  Sasahara, Kenji; Morigaki, Kenichi; Shinya, Kyoko
  Physical Chemistry Chemical Physics (2013), 15 (23), 8929-8939CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
  Alzheimer's disease (AD) is the most prevalent age-dependent form of dementia, characterized by extracellular amyloid deposits comprising amyloid β-peptide (Aβ) in the cerebral cortex. Increasing evidence has indicated that ganglioside GM1 (GM1) in lipid rafts plays a pivotal role in amyloid deposition of Aβ and the related cytotoxicity in AD. Despite recent efforts to characterize Aβ-lipid interactions, the effect of Aβ aggregation on dynamic properties and organization of lipid membranes is poorly understood. In this study, we examd. the aggregation of Aβ on supported lipid bilayers contg. raft components (i.e., cholesterol, sphingomyelin, and GM1) and its effects on the membrane properties. We showed that the lateral fluidity of membranes was significantly affected by membrane binding and subsequent aggregation of Aβ. Microscopic observations of the membrane surfaces demonstrated an enhancement in phase sepn. of lipids as a result of interactions between Aβ and GM1 during induced aggregation of Aβ. The uptake of GM1 into Aβ aggregates and the attendant membrane damage were also obsd. under a microscope when the membrane-anchored aggregates were formed. On the basis of these observations, we propose that Aβ aggregates formed in the presence of lipid membranes have a latent ability to trigger the uptake of raft components accompanied by phase sepn. of lipids.
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71. 71
  Khondker, A.; Alsop, R. J.; Rheinstädter, M. C. Membrane-Accelerated Amyloid-β Aggregation and Formation of Cross-β Sheets. Membranes 2017, 7, 49, DOI: 10.3390/membranes7030049
  71
  Membrane-accelerated amyloid-β aggregation and formation of cross-β sheets
  Khondker, Adree; Alsop, Richard J.; Rheinstadter, Maikel C.
  Membranes (Basel, Switzerland) (2017), 7 (3), 49/1-49/19CODEN: MBSEB6; ISSN:2077-0375. (MDPI AG)
  Amyloid-β aggregates play a causative role in Alzheimer's disease. These aggregates are a product of the phys. environment provided by the basic neuronal membrane, composed of a lipid bilayer. The intrinsic properties of the lipid bilayer allow amyloid-β peptides to nucleate and form well-ordered cross-β sheets within the membrane. Here, we correlate the aggregation of the hydrophobic fragment of the amyloid-β protein, Aβ, with the hydrophobicity, fluidity, and charge d. of a lipid bilayer. We summarize recent biophys. studies of model membranes and relate these to the process of aggregation in physiol. systems.
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72. 72
  Sciacca, M. F. M.; Pappalardo, M.; Attanasio, F.; Milardi, D.; Rosa, C. L.; Grasso, D. M. Are Fibril Growth and Membrane Damage Linked Processes? An Experimental and Computational Study of IAPP12–18 and IAPP21–27 Peptides. New J. Chem. 2010, 34, 200– 207, DOI: 10.1039/B9NJ00253G
  72
  Are fibril growth and membrane damage linked processes? An experimental and computational study of IAPP12-18 and IAPP21-27 peptides
  Sciacca, Michele F. M.; Pappalardo, Matteo; Attanasio, Francesco; Milardi, Danilo; La Rosa, Carmelo; Grasso, Domenico M.
  New Journal of Chemistry (2010), 34 (2), 200-207CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
  Islet amyloid polypeptide (IAPP) is a 37-residue hormone known to deposit as fibrillar aggregates in pancreatic β-cells of patients affected by T2DM. Although it has been proposed that both the fibrillogenic potential and membrane-activity may play a key role in IAPP cytotoxicity, a direct causative relationship between these two properties has not yet been firmly established. More recently, it has been obsd. that membrane damage may occur independently from fiber formation of IAPP and that these properties may be encoded by different sequences of IAPP. To further check this hypothesis, the membrane-activity and aggregation properties of the two neutral segments LANFLVH (IAPP12-18) and NNFGAIL (IAPP21-27), that recent theor. studies have reported to possess the highest and the lowest fibrillogenic potential resp., have been studied by means of a combined exptl. and computational approach. The whole of the results demonstrate that if neutral peptides and lipids are employed, the most fibrillogenic peptide has the lowest membrane damaging effect and vice versa. These findings are expected to contribute to our rational understanding of the factors involved in the formation of amyloidosis and in the mechanisms of peptide-induced membrane damage.
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73. 73
  Sciacca, M.; Milardi, D.; Pappalardo, M.; Rosa, C. L.; Grasso, D. Role of Electrostatics in the Thermal Stability of Ubiquitin: A Combined DSC and MM Study. J. Therm. Anal. Calorim. 2006, 86, 311– 314, DOI: 10.1007/s10973-005-7467-0
  73
  Role of electrostatics in the thermal stability of ubiquitin: a combined DSC and MM study
  Sciacca, M. F. M.; Milardi, D.; Pappalardo, M.; La Rosa, C.; Grasso, D. M.
  Journal of Thermal Analysis and Calorimetry (2006), 86 (2), 311-314CODEN: JTACF7; ISSN:1388-6150. (Springer)
  The failure of the ubiquitin-proteasome system is involved in many diseases. Here, in order to assess the pH-induced changes in the physico-chem. properties of ubiquitin, DSC measurements have been carried out at 2.5<pH<7. Parallel 'in silico' pH titrns., suggest that there is a direct relationship between the calorimetric data and the electrostatic properties of ubiquitin. It is suggested that these pH-induced changes in the properties of ubiquitin may play a role in detg. its ability to properly conjugate with its physiol. targets.
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74. 74
  Grasso, D.; Grasso, G.; Guantieri, V.; Impellizzeri, G.; Rosa, C. L.; Milardi, D.; Micera, G.; Õsz, K.; Pappalardo, G.; Rizzarelli, E.; Sanna, D.; Sóvágó, I. Environmental Effects on a Prion’s Helix II Domain: Copper(II) and Membrane Interactions with PrP180–193 and Its Analogues. Chem. – Eur. J. 2006, 12, 537– 547, DOI: 10.1002/chem.200500534
  74
  Environmental effects on a prion's helix II domain: Copper(II) and membrane interactions with PrP180-193 and its analogues
  Grasso, Domenico; Grasso, Giulia; Guantieri, Valeria; Impellizzeri, Giuseppe; La Rosa, Carmelo; Milardi, Danilo; Micera, Giovanni; Osz, Katalin; Pappalardo, Giuseppe; Rizzarelli, Enrico; Sanna, Daniele; Sovago, Imre
  Chemistry - A European Journal (2006), 12 (2), 537-547CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  An abnormal interaction between copper and the prion protein is believed to play a pivotal role in the pathogenesis of prion diseases. Copper binding has been mainly attributed to the N-terminal domain of the prion protein, but this hypothesis has recently been challenged in some papers which suggest that the C-terminal domain might also compete for metal anchoring. In particular, the segment corresponding to the helix II region of the prion protein, namely PrP180-193, has been shown both to bind copper and to exhibit a copper-enhanced cytotoxicity, as well as to interact with artificial membranes. The present work is aimed at extending these results by choosing the most representative model of this domain and by detg. its copper affinity. With this aim, the different role played by the electrostatic properties of the C- and N-termini of PrP180-193 (VNITIKQHTVTTTT) in detg. its conformational behavior, copper coordination and ability to perturb model membranes was investigated. Owing to the low soly. of PrP180-193, its copper affinity was evaluated by using the shorter PrPAc184-188NH2 (IKQHT) analog as a model. ESI-MS, ESR, UV/Vis, and CD measurements were carried out on the copper(II)/PrPAc184-188NH2 and copper(II)/PrP180-193NH2 systems, and showed that PrPAc184-188NH2 is a reliable model for the metal interaction with the helix II domain. The affinity of copper(II) for the helix II fragment is higher than that for the octarepeat and PrP106-126 peptides. Finally, the different ability of PrP180-193 analogs to perturb the DPPC model membrane was assessed by DSC measurements. The possible biol. consequences of these findings are also discussed briefly.
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75. 75
  Sciacca, M. F. M.; Pappalardo, M.; Milardi, D.; Grasso, D. M.; Rosa, C. L. Calcium-Activated Membrane Interaction of the Islet Amyloid Polypeptide: Implications in the Pathogenesis of Type II Diabetes Mellitus. Arch. Biochem. Biophys. 2008, 477, 291– 298, DOI: 10.1016/j.abb.2008.06.018
  75
  Calcium-activated membrane interaction of the islet amyloid polypeptide: Implications in the pathogenesis of type II diabetes mellitus
  Sciacca, Michele F. M.; Pappalardo, Matteo; Milardi, Danilo; Grasso, Domenico M.; La Rosa, Carmelo
  Archives of Biochemistry and Biophysics (2008), 477 (2), 291-298CODEN: ABBIA4; ISSN:0003-9861. (Elsevier Inc.)
  The role played by Ca2+ ions in the interaction of the human islet amyloid polypeptide (hIAPP) with model membranes has been investigated by differential scanning calorimetry (DSC) and CD expts. In particular, the interaction of hIAPP and its rat isoform (rIAPP) with zwitterionic dipalmitoyl-phosphatidylcholine (DPPC), neg. charged dipalmitoyl-phosphatidylserine (DPPS) vesicles and with a 3:1 mixts. of them, has been studied in the presence of Ca2+ ions. The expts. have evidenced that amorphous, sol. hIAPP assemblies interact with the hydrophobic core of DPPC bilayers. Conversely, the presence of Ca2+ ions is necessary to activate a preferential interaction of hIAPP with the hydrophobic core of DPPS membranes. These findings support the hypothesis that an impaired cellular homeostasis of Ca2+ ions may promote the insertion of hIAPP into the hydrophobic core of carrier vesicles which is thought to contribute to an eventual intracellular accumulation of β-sheet rich hIAPP aggregates.
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76. 76
  Milardi, D.; Sciacca, M. F. M.; Pappalardo, M.; Grasso, D. M.; La Rosa, C. The Role of Aromatic Side-Chains in Amyloid Growth and Membrane Interaction of the Islet Amyloid Polypeptide Fragment LANFLVH. Eur. Biophys. J. 2011, 40, 1– 12, DOI: 10.1007/s00249-010-0623-x
  76
  The role of aromatic side-chains in amyloid growth and membrane interaction of the islet amyloid polypeptide fragment LANFLVH
  Milardi, Danilo; Sciacca, Michele F. M.; Pappalardo, Matteo; Grasso, Domenico M.; Rosa, Carmelo
  European Biophysics Journal (2011), 40 (1), 1-12CODEN: EBJOE8; ISSN:0175-7571. (Springer)
  Human islet amyloid polypeptide (hIAPP) is known to misfold and aggregate into amyloid deposits that may be found in pancreatic tissues of patients affected by type 2 diabetes. Recent studies showed that the highly amyloidogenic peptide LANFLVH, corresponding to the N-terminal 12-18 region of IAPP, does not induce membrane damage. Here the authors assess the role played by the arom. residue Phe in driving both amyloid formation and membrane interaction of LANFLVH. To this aim, a set of variant heptapeptides in which the arom. residue Phe has been substituted with a Leu and Ala was studied. DSC and membrane-leakage expts. demonstrated that Phe substitution noticeably affects the peptide-induced changes in the thermotropic properties of the lipid bilayer but not its membrane damaging potential. Atomic force microscopy (AFM), ThT fluorescence and Congo red birefringence assays evidenced that the Phe residue is not required for fibrillogenesis, but it can influence the self-assembling kinetics. Mol. dynamics simulations have paralleled the outcome of the exptl. trials also providing informative details about the structure of the different peptide assemblies. These results support a general theory suggesting that arom. residues, although capable of affecting the self-assembly kinetics of small peptides and peptide-membrane interactions, are not essential either for amyloid formation or membrane leakage, and indicate that other factors such as β-sheet propensity, size and hydrophobicity of the side chain act synergistically to det. peptide properties.
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77. 77
  Di Natale, G.; Pappalardo, G.; Milardi, D.; Sciacca, M. F. M.; Attanasio, F.; La Mendola, D.; Rizzarelli, E. Membrane Interactions and Conformational Preferences of Human and Avian Prion N-Terminal Tandem Repeats: The Role of Copper(II) Ions, PH, and Membrane Mimicking Environments. J. Phys. Chem. B 2010, 114, 13830– 13838, DOI: 10.1021/jp1033036
  77
  Membrane Interactions and Conformational Preferences of Human and Avian Prion N-Terminal Tandem Repeats: The Role of Copper(II) Ions, pH, and Membrane Mimicking Environments
  Di Natale, Giuseppe; Pappalardo, Giuseppe; Milardi, Danilo; Sciacca, Michele F. M.; Attanasio, Francesco; La Mendola, Diego; Rizzarelli, Enrico
  Journal of Physical Chemistry B (2010), 114 (43), 13830-13838CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
  The flexible N-terminal domain of the prion protein (PrPc) is believed to play a pivotal role in both trafficking of the protein through the cell membrane and its pathogenic conversion into the β sheet-rich scrapie isoform (PrPsc). Unlike mammalian PrPc, avian prion proteins are not known to undergo any pathogenic conformational conversions. Consequently, some crit. advances in our understanding of the mol. mechanisms underlying prion pathogenesis are expected from comparative studies of the biophys. properties of the N-terminal domains of the two proteins. The present study addresses the role played by different environmental factors, i.e., copper(II), pH, and membrane-mimicking environments, in assisting the conformational preferences of huPrP60-91 and chPrP53-76, two sol. peptides encompassing the N-terminal copper(II) binding domains of the human and chicken prion proteins, resp. Moreover, the membrane interactions of huPrP60-91, chPrP53-76, and their copper(II) complexes were evaluated by Trp fluorescence in conjunction with measurements of the variation in thermotropic properties of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) unilamellar vesicles. CD expts. revealed that huPrP60-91 adopts a predominant polyproline II conformation in aq. soln. that is destabilized at basic pH or in the presence of trifluoroethanol (TFE). Unlike anionic sodium dodecyl sulfate (SDS), which seems to stabilize the polyproline II conformation further, zwitterionic dodecylphosphocholine (DPC) micelles do not affect the peptide structure. On the contrary, copper(II) promptly promotes an increase in β-turn-rich structures. Differential scanning calorimetry (DSC) and Trp fluorescence assays carried out on DPPC model membranes after incubation with huPrP60-91 showed a marked tendency of the peptide to slowly penetrate the lipid bilayer with a concomitant conformational transition toward an extended β-sheet-like structure. Such an event, which was ascribed to the hydrophobic Trp side chain residues, was shown to also depend on the level of copper(II) occupancy along the peptide. Conversely, the CD spectra of chPrP53-76 aq. solns. indicated the presence of a mixt. of random-coil/β-turn-like structures whose resulting equil. was influenced by SDS and copper(II) addn. Furthermore, chPrP53-76 did not exhibit any tendency to interact with model membranes in either the presence or absence of copper(II). The results reported here provide evidence of the different roles played by environmental factors in affecting the conformation and membrane activity of human and avian prion N-terminal domains.
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78. 78
  Sciacca, M. F. M.; Kotler, S. A.; Brender, J. R.; Chen, J.; Lee, D.; Ramamoorthy, A. Two-Step Mechanism of Membrane Disruption by Aβ through Membrane Fragmentation and Pore Formation. Biophys. J. 2012, 103, 702– 710, DOI: 10.1016/j.bpj.2012.06.045
  78
  Two-Step Mechanism of Membrane Disruption by Aβ through Membrane Fragmentation and Pore Formation
  Sciacca, Michele F. M.; Kotler, Samuel A.; Brender, Jeffrey R.; Chen, Jennifer; Lee, Dong-kuk; Ramamoorthy, Ayyalusamy
  Biophysical Journal (2012), 103 (4), 702-710CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
  Disruption of cell membranes by Aβ is believed to be one of the key components of Aβ toxicity. However, the mechanism by which this occurs is not fully understood. Here, we demonstrate that membrane disruption by Aβ occurs by a two-step process, with the initial formation of ion-selective pores followed by nonspecific fragmentation of the lipid membrane during amyloid fiber formation. Immediately after the addn. of freshly dissolved Aβ1-40, defects form on the membrane that share many of the properties of Aβ channels originally reported from single-channel elec. recording, such as cation selectivity and the ability to be blockaded by zinc. By contrast, subsequent amyloid fiber formation on the surface of the membrane fragments the membrane in a way that is not cation selective and cannot be stopped by zinc ions. Moreover, we obsd. that the presence of ganglioside enhances both the initial pore formation and the fiber-dependent membrane fragmentation process. Whereas pore formation by freshly dissolved Aβ1-40 is weakly obsd. in the absence of gangliosides, fiber-dependent membrane fragmentation can only be obsd. in their presence. These results provide insights into the toxicity of Aβ and may aid in the design of specific compds. to alleviate the neurodegeneration of Alzheimer's disease.
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79. 79
  Sciacca, M. F. M.; Brender, J. R.; Lee, D.-K.; Ramamoorthy, A. Phosphatidylethanolamine Enhances Amyloid Fiber-Dependent Membrane Fragmentation. Biochemistry 2012, 51, 7676– 7684, DOI: 10.1021/bi3009888
  79
  Phosphatidylethanolamine Enhances Amyloid Fiber-Dependent Membrane Fragmentation
  Sciacca, Michele F. M.; Brender, Jeffrey R.; Lee, Dong-Kuk; Ramamoorthy, Ayyalusamy
  Biochemistry (2012), 51 (39), 7676-7684CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
  The toxicity of amyloid-forming peptides has been hypothesized to reside in the ability of protein oligomers to interact with and disrupt the cell membrane. Much of the evidence for this hypothesis comes from in vitro expts. using model membranes. However, the accuracy of this approach depends on the ability of the model membrane to accurately mimic the cell membrane. The effect of membrane compn. has been overlooked in many studies of amyloid toxicity in model systems. By combining measurements of membrane binding, membrane permeabilization, and fiber formation, we show that lipids with the phosphatidylethanolamine (PE) headgroup strongly modulate the membrane disruption induced by IAPP (islet amyloid polypeptide protein), an amyloidogenic protein involved in type II diabetes. Our results suggest that PE lipids hamper the interaction of prefibrillar IAPP with membranes but enhance the membrane disruption correlated with the growth of fibers on the membrane surface via a detergent-like mechanism. These findings provide insights into the mechanism of membrane disruption induced by IAPP, suggesting a possible role of PE and other amyloids involved in other pathologies.
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80. 80
  Sciacca, M. F. M.; Milardi, D.; Messina, G. M. L.; Marletta, G.; Brender, J. R.; Ramamoorthy, A.; La Rosa, C. Cations as Switches of Amyloid-Mediated Membrane Disruption Mechanisms: Calcium and IAPP. Biophys. J. 2013, 104, 173– 184, DOI: 10.1016/j.bpj.2012.11.3811
  80
  Cations as switches of amyloid-mediated membrane disruption mechanisms: Calcium and IAPP
  Sciacca, Michele F. M.; Milardi, Danilo; Messina, Grazia M. L.; Marletta, Giovanni; Brender, Jeffrey R.; Ramamoorthy, Ayyalusamy; La Rosa, Carmelo
  Biophysical Journal (2013), 104 (1), 173-184CODEN: BIOJAU; ISSN:0006-3495. (Cell Press)
  Disruption of the integrity of the plasma membrane by amyloidogenic proteins is linked to the pathogenesis of a no. of common age-related diseases. Although accumulating evidence suggests that adverse environmental stressors such as unbalanced levels of metal ions may trigger amyloid-mediated membrane damage, many features of the mol. mechanisms underlying these events are unknown. Here, using human islet amyloid polypeptide (hIAPP, aka amylin), an amyloidogenic peptide assocd. with β-cell death in type 2 diabetes, the authors demonstrate that the presence of Ca2+ inhibits membrane damage occurring immediately after the interaction of freshly dissolved hIAPP with the membrane, but significantly enhances fiber-dependent membrane disruption. In particular, dye leakage, quartz crystal microbalance, at. force microscopy, and NMR expts. showed that Ca2+ promoted a shallow membrane insertion of hIAPP, which led to the removal of lipids from the bilayer through a detergent-like mechanism triggered by fiber growth. Because both types of membrane-damage mechanisms are common to amyloid toxicity by most amyloidogenic proteins, it is likely that unregulated ion homeostasis, amyloid aggregation, and membrane disruption are all parts of a self-perpetuating cycle that fuels amyloid cytotoxicity.
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  Sciacca, M. F.; Monaco, I.; Rosa, C. L.; Milardi, D. The Active Role of Ca 2+ Ions in Aβ-Mediated Membrane Damage. Chem. Commun. 2018, 54, 3629– 3631, DOI: 10.1039/C8CC01132J
  81
  The active role of Ca2+ ions in Aβ-mediated membrane damage
  Sciacca, Michele F. M.; Monaco, Irene; La Rosa, Carmelo; Milardi, Danilo
  Chemical Communications (Cambridge, United Kingdom) (2018), 54 (29), 3629-3631CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  Ca2+ dysregulation, membrane leakage, and amyloid-β (Aβ) growth are hallmarks of Alzheimer's disease. Here, we show that Ca2+ ions inhibit membrane damage due to amyloid channels, but enhance membrane disruption assocd. with fibers growing on the lipid surface. The similarities with IAPP suggest that this may represent a mechanism common to all proteinopathies.
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  Mroczko, B.; Groblewska, M.; Litman-Zawadzka, A.; Kornhuber, J.; Lewczuk, P. Amyloid β Oligomers (AβOs) in Alzheimer’s Disease. J. Neural Transm. 2018, 125, 177– 191, DOI: 10.1007/s00702-017-1820-x
  82
  Amyloid β oligomers (AβOs) in Alzheimer's disease
  Mroczko, Barbara; Groblewska, Magdalena; Litman-Zawadzka, Ala; Kornhuber, Johannes; Lewczuk, Piotr
  Journal of Neural Transmission (2018), 125 (2), 177-191CODEN: JNTRF3; ISSN:0300-9564. (Springer-Verlag GmbH)
  A review. The causative role of amyloid β 1-42 (Aβ42) aggregation in the pathogenesis of Alzheimer's disease (AD) has been under debate for over 25 years. Primarily, scientific efforts have focused on the dyshomeostasis between prodn. and clearance of Aβ42. This imbalance may result from mutations either in genes for the substrate, i.e., amyloid precursor protein or in genes encoding presenilin, the enzyme of the reaction that generates Aβ42. Currently, it is supposed that sol. oligomers of amyloid beta (AβOs) and not fibrillar Aβ42 within neuritic plaques may be the toxic factors acting on a very early stage of AD, perhaps even initiating pathol. cascade. For example, sol. AβOs isolated from AD patients brains reduced no. of synapses, inhibited long-term potentiation, and enhanced long-term synaptic depression in brain regions responsible for memory in animal models of AD. Concns. of AβOs in the cerebrospinal fluid (CSF) of AD patients are often reported higher than in non-demented controls, and show a neg. correlation with mini-mental state examn. scores. Furthermore, increased Aβ42/oligomer ratio in the CSF of AD/MCI patients indicated that the presence of sol. AβOs in CSF may be linked to lowering of natively measured monomeric Aβ42 by epitopes masking, and hence, concns. of AβOs in the CSF are postulated to as useful AD biomarkers.
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  Nitta, A.; Itoh, A.; Hasegawa, T.; Nabeshima, T. Beta-Amyloid Protein-Induced Alzheimer’s Disease Animal Model. Neurosci. Lett. 1994, 170, 63– 66, DOI: 10.1016/0304-3940(94)90239-9
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  β-Amyloid protein-induced Alzheimer's disease animal model
  Nitta, Atsumi; Itoh, Akio; Hasegawa, Takaaki; Nabeshima, Toshitaka
  Neuroscience Letters (1994), 170 (1), 63-6CODEN: NELED5; ISSN:0304-3940.
  To investigate the toxicity of β-amyloid protein (which constitutes senile plaques of Alzheimer's disease (AD)), synthesized human β-amyloid(1-40) was infused into cerebral ventricles of rats for 14 days by using mini-osmotic pump. The performance of the water maze task by the β-amyloid protein-treated rats was impaired. Choline acetyltransferase activity significantly decreased in the frontal cortex and hippocampus. These results suggest that the deposition of β-amyloid protein in the brain is related to the impairment of learning and cholinergic neuronal degeneration, and that β-amyloid protein-treated rats could be used as an animal model for AD.
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84. 84
  Flashka, H. A. in EDTA Titrations; Pergamon Press: London, 1959.
  There is no corresponding record for this reference.
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  Sciacca, M. F.; Lolicato, F.; Tempra, C.; Scollo, F.; Sahoo, B. R.; Watson, M. D.; García-Viñuales, S.; Milardi, D.; Raudino, A.; Lee, J. C.; Ramamoorthy, A.; La Rosa, C. Lipid-Chaperone Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins. ACS Chem. Neurosci. 2020, 11, 4336– 4350, DOI: 10.1021/acschemneuro.0c00588
  85
  Lipid-Chaperone Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins
  Sciacca, Michele F.; Lolicato, Fabio; Tempra, Carmelo; Scollo, Federica; Sahoo, Bikash R.; Watson, Matthew D.; Garcia-Vinuales, Sara; Milardi, Danilo; Raudino, Antonio; Lee, Jennifer C.; Ramamoorthy, Ayyalusamy; La Rosa, Carmelo
  ACS Chemical Neuroscience (2020), 11 (24), 4336-4350CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  An increasing no. of human diseases has been shown to be linked to aggregation and amyloid formation by intrinsically disordered proteins (IDPs). Amylin, amyloid-β, and α-synuclein are, indeed, involved in type-II diabetes, Alzheimer's, and Parkinson's, resp. Despite the correlation of the toxicity of these proteins at early aggregation stages with membrane damage, the mol. events underlying the process is quite complex to understand. In this study, we demonstrate the crucial role of free lipids in the formation of lipid-protein complex, which enables an easy membrane insertion for amylin, amyloid-β, and α-synuclein. Exptl. results from a variety of biophys. methods and mol. dynamics results reveal that this common mol. pathway in membrane poration is shared by amyloidogenic (amylin, amyloid-β, and α-synuclein) and nonamyloidogenic (rat IAPP, β-synuclein) proteins. Based on these results, we propose a "lipid-chaperone" hypothesis as a unifying framework for protein-membrane poration.
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  MacDonald, R. C.; MacDonald, R. I.; Menco, B. P.; Takeshita, K.; Subbarao, N. K.; Hu, L. R. Small-Volume Extrusion Apparatus for Preparation of Large, Unilamellar Vesicles. Biochim. Biophys. Acta 1991, 1061, 297– 303, DOI: 10.1016/0005-2736(91)90295-j
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  Small-volume extrusion apparatus for preparation of large, unilamellar vesicles
  MacDonald R C; MacDonald R I; Menco B P; Takeshita K; Subbarao N K; Hu L R
  Biochimica et biophysica acta (1991), 1061 (2), 297-303 ISSN:0006-3002.
  The design and performance of a filter holder which enables convenient preparation of volumes of up to a milliliter of large, unilamellar vesicles formed by extrusion (LUVETs) from multilamellar vesicles (MLVs) are described. The filter holder provides for back-and-forth passage of the sample between two syringes, a design that minimizes filter blockage, eliminates the need to change filters during LUVET preparation and reduces preparation time to a few minutes. Replicas of slam-frozen LUVETs in the electron microscope are unilamellar and reasonably homogeneous with an average diameter close to the pore size of the filters used to extrude them. Extrusion per se does not destabilize the vesicles, which trapped a fluorescent dye only when they were disrupted on freeze-thawing and during the first extrusion when most of the MLVs were apparently converted to LUVETs.
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  Stewart, J. C. Colorimetric Determination of Phospholipids with Ammonium Ferrothiocyanate. Anal. Biochem. 1980, 104, 10– 14, DOI: 10.1016/0003-2697(80)90269-9
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  Colorimetric determination of phospholipids with ammonium ferrothiocyanate
  Stewart, John Charles Marshall
  Analytical Biochemistry (1980), 104 (1), 10-14CODEN: ANBCA2; ISSN:0003-2697.
  Phospholipids may be measured colorimetrically (as dipalmitoyl lecithin) without conventional acid digestion and color development procedures by forming a complex with NH4 ferrothiocyanate.
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  Lambert, M. P.; Barlow, A. K.; Chromy, B. A.; Edwards, C.; Freed, R.; Liosatos, M.; Morgan, T. E.; Rozovsky, I.; Trommer, B.; Viola, K. L.; Wals, P.; Zhang, C.; Finch, C. E.; Krafft, G. A.; Klein, W. L. Diffusible, Nonfibrillar Ligands Derived from Abeta1-42 Are Potent Central Nervous System Neurotoxins. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 6448– 6453, DOI: 10.1073/pnas.95.11.6448
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  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins
  Lambert M P; Barlow A K; Chromy B A; Edwards C; Freed R; Liosatos M; Morgan T E; Rozovsky I; Trommer B; Viola K L; Wals P; Zhang C; Finch C E; Krafft G A; Klein W L
  Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (11), 6448-53 ISSN:0027-8424.
  Abeta1-42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer's pathogenesis. Neurotoxicity of amyloid beta protein (Abeta) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible Abeta oligomers (referred to as ADDLs, for Abeta-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer's disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Abeta-derived diffusible ligands acting upon particular neural signal transduction pathways.
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Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.1c00707.
- DSC thermograms, thermodynamic data and comparison, and ThT in the presence of model membranes (PDF)
- cn1c00707_si_001.pdf (282.74 kb)
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Semax, a Synthetic Regulatory Peptide, Affects Copper-Induced Abeta Aggregation and Amyloid Formation in Artificial Membrane ModelsClick to copy article linkArticle link copied!

ACS Chemical Neuroscience

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Abstract

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Introduction

Results and Discussion

Thioflavin T Assay in the Buffer Reveals Anti-aggregating Properties of Semax in the Presence of Cu2+

Figure 1

Semax Reduces the Abeta Oligomers Levels

Figure 2

Semax Prevents Aβ1–40 Interaction with the Hydrophobic Core of the Model Membrane in the Presence of Cu2+

Figure 3

Semax Strongly Inhibits Fiber Formation in the Presence of bTLE Model Membranes

Figure 4

Semax Prevents Membrane Disruption Induced by Aβ1–40

Figure 5

Semax Rescues Abeta and Cu-Associated Abeta Toxicity

Figure 6

Conclusions

Material and Methods

Materials

Preparation of the Artificial Cerebrospinal Fluid

Peptide Preparation

LUV Preparation

ThT Measurements

Dye Leakage Measurements

DSC Experiments

Anti-oligomerization Assay

Western Blot Analysis

Cell Maintenance and Treatment Protocol

MTT Assay

Supporting Information

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Abstract

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References

Supporting Information

Supporting Information

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Semax, a Synthetic Regulatory Peptide, Affects Copper-Induced Abeta Aggregation and Amyloid Formation in Artificial Membrane Models
Click to copy article linkArticle link copied!

Thioflavin T Assay in the Buffer Reveals Anti-aggregating Properties of Semax in the Presence of Cu²⁺

Semax Prevents Aβ_1–40 Interaction with the Hydrophobic Core of the Model Membrane in the Presence of Cu²⁺

Semax Prevents Membrane Disruption Induced by Aβ_1–40